Pesticidal compositions and processes related thereto

ABSTRACT

This document discloses molecules having the following formula (“Formula One”): 
     
       
         
         
             
             
         
       
     
     and processes related thereto.

CROSS REFERENCES TO RELATED APPLICATIONS

This application is a continuation of U.S. non-provisional applicationSer. No. 13/788,850, which was filed on Mar. 7, 2013, which claimspriority from, and benefit of, U.S. provisional application Ser. No.61/639,274, which was filed on Apr. 27, 2012. The entire contents ofthese applications is hereby incorporated by reference into thisapplication.

FIELD OF THE DISCLOSURE

This disclosure is related to the field of processes to producemolecules that are useful as pesticides (e.g., acaricides, insecticides,molluscicides, and nematicides), such molecules, and processes of usingsuch molecules to control pests.

BACKGROUND

Pests cause millions of human deaths around the world each year.Furthermore, there are more than ten thousand species of pests thatcause losses in agriculture. The world-wide agricultural losses amountto billions of U.S. dollars each year.

Termites cause damage to all kinds of private and public structures. Theworld-wide termite damage losses amount to billions of U.S. dollars eachyear.

Stored food pests eat and adulterate stored food. The world-wide storedfood losses amount to billions of U.S. dollars each year, but moreimportantly, deprive people of needed food.

There is an acute need for new pesticides. Certain pests are developingresistance to pesticides in current use. Hundreds of pest species areresistant to one or more pesticides. The development of resistance tosome of the older pesticides, such as DDT, the carbamates, and theorganophosphates, is well known. But resistance has even developed tosome of the newer pesticides.

Therefore, for many reasons, including the above reasons, a need existsfor new pesticides.

DEFINITIONS

The examples given in the definitions are generally non-exhaustive andmust not be construed as limiting the invention disclosed in thisdocument. It is understood that a substituent should comply withchemical bonding rules and steric compatibility constraints in relationto the particular molecule to which it is attached.

“Alkenyl” means an acyclic, unsaturated (at least one carbon-carbondouble bond), branched or unbranched, substituent consisting of carbonand hydrogen, for example, vinyl, allyl, butenyl, pentenyl, and hexenyl.

“Alkenyloxy” means an alkenyl further consisting of a carbon-oxygensingle bond, for example, allyloxy, butenyloxy, pentenyloxy, hexenyloxy.

“Alkoxy” means an alkyl further consisting of a carbon-oxygen singlebond, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy,isobutoxy, and tert-butoxy.

“Alkyl” means an acyclic, saturated, branched or unbranched, substituentconsisting of carbon and hydrogen, for example, methyl, ethyl, (C₃)alkylwhich represents n-propyl and isopropyl), (C₄)alkyl which representsn-butyl, sec-butyl, isobutyl, and tert-butyl.

“Alkynyl” means an acyclic, unsaturated (at least one carbon-carbontriple bond), branched or unbranched, substituent consisting of carbonand hydrogen, for example, ethynyl, propargyl, butynyl, and pentynyl.

“Alkynyloxy” means an alkynyl further consisting of a carbon-oxygensingle bond, for example, pentynyloxy, hexynyloxy, heptynyloxy, andoctynyloxy.

“Aryl” means a cyclic, aromatic substituent consisting of hydrogen andcarbon, for example, phenyl, naphthyl, and biphenyl.

“(C_(x)-C_(y))” where the subscripts “x” and “y” are integers such as 1,2, or 3, means the range of carbon atoms for a substituent—for example,(C₁-C₄)alkyl means methyl, ethyl, n-propyl, isopropyl, n-butyl,sec-butyl, isobutyl, and tert-butyl, each individually.

“Cycloalkenyl” means a monocyclic or polycyclic, unsaturated (at leastone carbon-carbon double bond) substituent consisting of carbon andhydrogen, for example, cyclobutenyl, cyclopentenyl, cyclohexenyl,norbornenyl, bicyclo[2.2.2]octenyl, tetrahydronaphthyl,hexahydronaphthyl, and octahydronaphthyl.

“Cycloalkenyloxy” means a cycloalkenyl further consisting of acarbon-oxygen single bond, for example, cyclobutenyloxy,cyclopentenyloxy, norbornenyloxy, and bicyclo[2.2.2]octenyloxy.

“Cycloalkyl” means a monocyclic or polycyclic, saturated substituentconsisting of carbon and hydrogen, for example, cyclopropyl, cyclobutyl,cyclopentyl, norbornyl, bicyclo[2.2.2]octyl, and decahydronaphthyl.

“Cycloalkoxy” means a cycloalkyl further consisting of a carbon-oxygensingle bond, for example, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy,norbornyloxy, and bicyclo[2.2.2]octyloxy.

“Halo” means fluoro, chloro, bromo, and iodo.

“Haloalkoxy” means an alkoxy further consisting of, from one to themaximum possible number of identical or different, halos, for example,fluoromethoxy, trifluoromethoxy, 2,2-difluoropropoxy, chloromethoxy,trichloromethoxy, 1,1,2,2-tetrafluoroethoxy, and pentafluoroethoxy.

“Haloalkyl” means an alkyl further consisting of, from one to themaximum possible number of, identical or different, halos, for example,fluoromethyl, trifluoromethyl, 2,2-difluoropropyl, chloromethyl,trichloromethyl, and 1,1,2,2-tetrafluoroethyl.

“Heterocyclyl” means a cyclic substituent that may be fully saturated,partially unsaturated, or fully unsaturated, where the cyclic structurecontains at least one carbon and at least one heteroatom, where saidheteroatom is nitrogen, sulfur, or oxygen. In the case of sulfur, thatatom can be in other oxidation states such as a sulfoxide and sulfone.Examples of aromatic heterocyclyls include, but are not limited to,benzofuranyl, benzoisothiazolyl, benzoisoxazolyl, benzoxazolyl,benzothienyl, benzothiazolyl, cinnolinyl, furanyl, imidazolyl,indazolyl, indolyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl,oxadiazolyl, oxazolinyl, oxazolyl, phthalazinyl, pyrazinyl, pyrazolinyl,pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl,quinolinyl, quinoxalinyl, tetrazolyl, thiazolinyl, thiazolyl, thienyl,triazinyl, and triazolyl. Examples of fully saturated heterocyclylsinclude, but are not limited to, piperazinyl, piperidinyl, morpholinyl,pyrrolidinyl, oxetanyl, tetrahydrofuranyl, tetrahydrothienyl andtetrahydropyranyl. Examples of partially unsaturated heterocyclylsinclude, but are not limited to, 1,2,3,4-tetrahydroquinolinyl,4,5-dihydro-oxazolyl, 4,5-dihydro-1H-pyrazolyl, 4,5-dihydro-isoxazolyl,and 2,3-dihydro-[1,3,4]-oxadiazolyl. Additional examples include thefollowing

DETAILED DESCRIPTION

This document discloses molecules having the following formula (“FormulaOne”):

wherein

(a) A is either

(b) R1 is H, F, Cl, Br, I, CN, NO₂, substituted or unsubstituted C₁-C₆alkyl, substituted or unsubstituted C₂-C₆ alkenyl, substituted orunsubstituted C₁-C₆ alkoxy, substituted or unsubstituted C₂-C₆alkenyloxy, substituted or unsubstituted C₃-C₁₀ cycloalkyl, substitutedor unsubstituted C₃-C₁₀ cycloalkenyl, substituted or unsubstitutedC₆-C₂₀ aryl, substituted or unsubstituted C₁-C₂₀ heterocyclyl, OR9,C(=X1)R9, C(=X1)OR9, C(=X1)N(R9)₂, N(R9)₂, N(R9)C(=X1)R9, S(O)_(n)R9,S(O)_(n)OR9, S(O)_(n)N(R9)₂, or R9S(O)_(n)R9,

-   -   wherein each said R1, which is substituted, has one or more        substituents selected from F, Cl, Br, I, CN, NO₂, C₁-C₆ alkyl,        C₂-C₆ alkenyl, C₁-C₆ haloalkyl, C₂-C₆ haloalkenyl, C₁-C₆        haloalkyloxy, C₂-C₆ haloalkenyloxy, C₃-C₁₀ cycloalkyl, C₃-C₁₀        cycloalkenyl, C₃-C₁₀ halocycloalkyl, C₃-C₁₀ halocycloalkenyl,        OR9, S(O)_(n)OR9, C₆-C₂₀ aryl, or C₁-C₂₀ heterocyclyl, (each of        which that can be substituted, may optionally be substituted        with R9);

(c) R2 is H, F, Cl, Br, I, CN, NO₂, substituted or unsubstituted C₁-C₆alkyl, substituted or unsubstituted C₂-C₆ alkenyl, substituted orunsubstituted C₁-C₆ alkoxy, substituted or unsubstituted C₂-C₆alkenyloxy, substituted or unsubstituted C₃-C₁₀ cycloalkyl, substitutedor unsubstituted C₃-C₁₀ cycloalkenyl, substituted or unsubstitutedC₆-C₂₀ aryl, substituted or unsubstituted C₁-C₂₀ heterocyclyl, OR9,C(=X1)R9, C(=X1)OR9, C(=X1)N(R9)₂, N(R9)₂, N(R9)C(=X1)R9, SR9,S(O)_(n)OR9, or R9S(O)_(n)R9,

-   -   wherein each said R2, which is substituted, has one or more        substituents selected from F, Cl, Br, I, CN, NO₂, C₁-C₆ alkyl,        C₂-C₆ alkenyl, C₁-C₆ haloalkyl, C₂-C₆ haloalkenyl, C₁-C₆        haloalkyloxy, C₂-C₆ haloalkenyloxy, C₃-C₁₀ cycloalkyl, C₃-C₁₀        cycloalkenyl, C₃-C₁₀ halocycloalkyl, C₃-C₁₀ halocycloalkenyl,        OR9, S(O)_(n)OR9, C₆-C₂₀ aryl, or C₁-C₂₀ heterocyclyl, (each of        which that can be substituted, may optionally be substituted        with R9);

(d) R3 is H, F, Cl, Br, I, CN, NO₂, substituted or unsubstituted C₁-C₆alkyl, substituted or unsubstituted C₂-C₆ alkenyl, substituted orunsubstituted C₁-C₆ alkoxy, substituted or unsubstituted C₂-C₆alkenyloxy, substituted or unsubstituted C₃-C₁₀ cycloalkyl, substitutedor unsubstituted C₃-C₁₀ cycloalkenyl, substituted or unsubstitutedC₆-C₂₀ aryl, substituted or unsubstituted C₁-C₂₀ heterocyclyl, OR9,C(=X1)R9, C(=X1)OR9, C(=X1)N(R9)₂, N(R9)₂, N(R9)C(=X1)R9, SR9,S(O)_(n)OR9, or R9S(O)_(n)R9,

-   -   wherein each said R3, which is substituted, has one or more        substituents selected from F, Cl, Br, I, CN, NO₂, C₁-C₆ alkyl,        C₂-C₆ alkenyl, C₁-C₆ haloalkyl, C₂-C₆ haloalkenyl, C₁-C₆        haloalkyloxy, C₂-C₆ haloalkenyloxy, C₃-C₁₀ cycloalkyl, C₃-C₁₀        cycloalkenyl, C₃-C₁₀ halocycloalkyl, C₃-C₁₀ halocycloalkenyl,        OR9, S(O)_(n)OR9, C₆-C₂₀ aryl, or C₁-C₂₀ heterocyclyl, (each of        which that can be substituted, may optionally be substituted        with R9);

(e) when A is

-   -   (1) A1 then A1 is either        -   (a) A11

-   -   where R4 is H, NO₂, substituted or unsubstituted C₁-C₆ alkyl,        substituted or unsubstituted C₂-C₆ alkenyl, substituted or        unsubstituted C₁-C₆ alkoxy, substituted or unsubstituted C₃-C₁₀        cycloalkyl, substituted or unsubstituted C₃-C₁₀ cycloalkenyl,        substituted or unsubstituted C₆-C₂₀ aryl, substituted or        unsubstituted C₁-C₂₀ heterocyclyl, C(=X1)R9, C(=X1)OR9,        C(=X1)N(R9)₂, N(R9)₂, N(R9)C(=X1)R9, S(O)_(n)OR9, or        R9S(O)_(n)R9,        -   wherein each said R4, which is substituted, has one or more            substituents selected from F, Cl, Br, I, CN, NO₂, C₁-C₆            alkyl, C₂-C₆ alkenyl, C₁-C₆ haloalkyl, C₂-C₆ haloalkenyl,            C₁-C₆ haloalkyloxy, C₂-C₆ haloalkenyloxy, C₃-C₁₀ cycloalkyl,            C₃-C₁₀ cycloalkenyl, C₃-C₁₀ halocycloalkyl, C₃-C₁₀            halocycloalkenyl, OR9, S(O)_(n)OR9, C₆-C₂₀ aryl, or C₁-C₂₀            heterocyclyl, (each of which that can be substituted, may            optionally be substituted with R9), or        -   (b) A12

-   -   where R4 is a C₁-C₆ alkyl,        -   (2) A2 then R4 is H, F, Cl, Br, I, CN, NO₂, substituted or            unsubstituted C₁-C₆ alkyl, substituted or unsubstituted            C₂-C₆ alkenyl, substituted or unsubstituted C₁-C₆ alkoxy,            substituted or unsubstituted C₂-C₆ alkenyloxy, substituted            or unsubstituted C₃-C₁₀ cycloalkyl, substituted or            unsubstituted C₃-C₁₀ cycloalkenyl, substituted or            unsubstituted C₆-C₂₀ aryl, substituted or unsubstituted            C₁-C₂₀ heterocyclyl, OR9, C(=X1)R9, C(=X1)OR9, C(=X1)N(R9)₂,            N(R9)₂, N(R9)C(=X1)R9, SR9, S(O)_(n)OR9, or R9S(O)_(n)R9,            -   wherein each said R4, which is substituted, has one or                more substituents selected from F, Cl, Br, I, CN, NO₂,                C₁-C₆ alkyl, C₂-C₆ alkenyl, C₁-C₆ haloalkyl, C₂-C₆                haloalkenyl, C₁-C₆ haloalkyloxy, C₂-C₆ haloalkenyloxy,                C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkenyl, C₃-C₁₀                halocycloalkyl, C₃-C₁₀ halocycloalkenyl, OR9,                S(O)_(n)OR9, C₆-C₂₀ aryl, or C₁-C₂₀ heterocyclyl, (each                of which that can be substituted, may optionally be                substituted with R9);

(f) R5 is H, F, Cl, Br, I, CN, NO₂, substituted or unsubstituted C₁-C₆alkyl, substituted or unsubstituted C₂-C₆ alkenyl, substituted orunsubstituted C₁-C₆ alkoxy, substituted or unsubstituted C₂-C₆alkenyloxy, substituted or unsubstituted C₃-C₁₀ cycloalkyl, substitutedor unsubstituted C₃-C₁₀ cycloalkenyl, substituted or unsubstitutedC₆-C₂₀ aryl, OR9, C(=X1)R9, C(=X1)OR9, C(=X1)N(R9)₂, N(R9)₂,N(R9)C(=X1)R9, SR9, S(O)_(n)OR9, or R9S(O)_(n)R9,

-   -   wherein each said R5, which is substituted, has one or more        substituents selected from F, Cl, Br, I, CN, NO₂, C₁-C₆ alkyl,        C₂-C₆ alkenyl, C₁-C₆ haloalkyl, C₂-C₆ haloalkenyl, C₁-C₆        haloalkyloxy, C₂-C₆ haloalkenyloxy, C₃-C₁₀ cycloalkyl, C₃-C₁₀        cycloalkenyl, C₃-C₁₀ halocycloalkyl, C₃-C₁₀ halocycloalkenyl,        OR9, S(O)_(n)OR9, or C₆-C₂₀ aryl, (each of which that can be        substituted, may optionally be substituted with R9);

(g)

-   -   (1) when A is A1 then R6 is R11, substituted or unsubstituted        C₁-C₆ alkyl, substituted or unsubstituted C₂-C₆ alkenyl,        substituted or unsubstituted C₁-C₆ alkoxy, substituted or        unsubstituted C₂-C₆ alkenyloxy, substituted or unsubstituted        C₃-C₁₀ cycloalkyl, substituted or unsubstituted C₃-C₁₀        cycloalkenyl, substituted or unsubstituted C₆-C₂₀ aryl,        substituted or unsubstituted C₁-C₂₀ heterocyclyl, OR9, C(=X1)R9,        C(=X1)OR9, C(=X1)N(R9)₂, N(R9)₂, N(R9)C(=X1)R9, SR9,        S(O)_(n)OR9, R9S(O)_(n)R9, C₁-C₆ alkyl C₆-C₂₀ aryl (wherein the        alkyl and aryl can independently be substituted or        unsubstituted), C(=X2)R9, C(=X1)X2R9, R9X2C(=X1)R9, R9X2R9,        C(═O)(C₁-C₆ alkyl)S(O)_(n)(C₁-C₆ alkyl), C(═O)(C₁-C₆        alkyl)C(═O)O(C₁-C₆ alkyl), (C₁-C₆ alkyl)OC(═O)(C₆-C₂₀ aryl),        (C₁-C₆ alkyl)OC(═O)(C₁-C₆ alkyl), C₁-C₆ alkyl-(C₃-C₁₀        cyclohaloalkyl), or (C₁-C₆ alkenyl)C(═O)O(C₁-C₆ alkyl), or        R9X2C(=X1)X2R9,        -   wherein each said R6 (except R11), which is substituted, has            one or more substituents selected from F, Cl, Br, I, CN,            NO₂, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₁-C₆ haloalkyl, C₂-C₆            haloalkenyl, C₁-C₆ haloalkyloxy, C₂-C₆ haloalkenyloxy,            C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkenyl, C₃-C₁₀            halocycloalkyl, C₃-C₁₀ halocycloalkenyl, OR9, S(O)_(n)OR9,            C₆-C₂₀ aryl, or C₁-C₂₀ heterocyclyl, R9aryl, (each of which            that can be substituted, may optionally be substituted with            R9),        -   optionally R6 (except R11) and R8 can be connected in a            cyclic arrangement, where optionally such arrangement can            have one or more heteroatoms selected from O, S, or, N, in            the cyclic structure connecting R6 and R8, and    -   (2) when A is A2 then R6 is R11, H, substituted or unsubstituted        C₁-C₆ alkyl, substituted or unsubstituted C₂-C₆ alkenyl,        substituted or unsubstituted C₁-C₆ alkoxy, substituted or        unsubstituted C₂-C₆ alkenyloxy, substituted or unsubstituted        C₃-C₁₀ cycloalkyl, substituted or unsubstituted C₃-C₁₀        cycloalkenyl, substituted or unsubstituted C₆-C₂₀ aryl,        substituted or unsubstituted C₁-C₂₀ heterocyclyl, OR9, C(=X1)R9,        C(=X1)OR9, C(=X1)N(R9)₂, N(R9)₂, N(R9)C(=X1)R9, SR9,        S(O)_(n)OR9, R9S(O)_(n)R9, C₁-C₆ alkyl C₆-C₂₀ aryl (wherein the        alkyl and aryl can independently be substituted or        unsubstituted), C(=X2)R9, C(=X1)X2R9, R9X2C(=X1)R9, R9X2R9,        C(═O)(C₁-C₆ alkyl)S(O)_(n)(C₁-C₆ alkyl), C(═O)(C₁-C₆        alkyl)C(═O)O(C₁-C₆ alkyl), (C₁-C₆ alkyl)OC(═O)(C₆-C₂₀ aryl),        (C₁-C₆ alkyl)OC(═O)(C₁-C₆ alkyl), C₁-C₆ alkyl-(C₃-C₁₀        cyclohaloalkyl), or (C₁-C₆ alkenyl)C(═O)O(C₁-C₆ alkyl), or        R9X2C(=X1)X2R9,        -   wherein each said R6 (except R11), which is substituted, has            one or more substituents selected from F, Cl, Br, I, CN,            NO₂, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₁-C₆ haloalkyl, C₂-C₆            haloalkenyl, C₁-C₆ haloalkyloxy, C₂-C₆ haloalkenyloxy,            C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkenyl, C₃-C₁₀            halocycloalkyl, C₃-C₁₀ halocycloalkenyl, OR9, S(O)_(n)OR9,            C₆-C₂₀ aryl, or C₁-C₂₀ heterocyclyl, R9aryl, (each of which            that can be substituted, may optionally be substituted with            R9),        -   optionally R6 (except R11) and R8 can be connected in a            cyclic arrangement, where optionally such arrangement can            have one or more heteroatoms selected from O, S, or N, in            the cyclic structure connecting R6 and R8;

(h) R7 is O, S, NR9, or NOR9;

(i) R8 is substituted or unsubstituted C₁-C₆ alkyl, substituted orunsubstituted C₂-C₆ alkenyl, substituted or unsubstituted C₁-C₆ alkoxy,substituted or unsubstituted C₂-C₆ alkenyloxy, substituted orunsubstituted C₃-C₁₀ cycloalkyl, substituted or unsubstituted C₃-C₁₀cycloalkenyl, substituted or unsubstituted C₆-C₂₀ aryl, substituted orunsubstituted C₁-C₂₀ heterocyclyl, OR9, OR9S(O)_(n)R9, C(=X1)R9,C(=X1)OR9, R9C(=X1)OR9, R9X2C(=X1)R9X2R9, C(=X1)N(R9)₂, N(R9)₂,N(R9)(R9S(O)_(n)R9), N(R9)C(=X1)R9, SR9, S(O)_(n)OR9, R9S(O)_(n)R9, orR9S(O)_(n)(NZ)R9,

-   -   wherein each said R8, which is substituted, has one or more        substituents selected from F, Cl, Br, I, CN, NO₂, C₁-C₆ alkyl,        C₂-C₆ alkenyl, C₁-C₆ haloalkyl, C₂-C₆ haloalkenyl, C₁-C₆        haloalkyloxy, C₂-C₆ haloalkenyloxy, C₃-C₁₀ cycloalkyl, C₃-C₁₀        cycloalkenyl, C₃-C₁₀ halocycloalkyl, C₃-C₁₀ halocycloalkenyl,        N(R9)S(O)_(n)R9, oxo, OR9, S(O)_(n)OR9, R9S(O)_(n)R9,        S(O)_(n)R9, C₆-C₂₀ aryl, or C₁-C₂₀ heterocyclyl, (each of which        that can be substituted, may optionally be substituted with R9)    -   alternatively R8 is R13-S(O)_(n)—R13 wherein each R13 is        independently selected from substituted or unsubstituted C₁-C₆        alkyl, substituted or unsubstituted C₂-C₆ alkenyl, substituted        or unsubstituted C₁-C₆ alkoxy, substituted or unsubstituted        C₂-C₆ alkenyloxy, substituted or unsubstituted C₃-C₁₀        cycloalkyl, substituted or unsubstituted C₃-C₁₀ cycloalkenyl,        substituted or unsubstituted C₆-C₂₀ aryl, substituted or        unsubstituted C₁-C₂₀ heterocyclyl, substituted or unsubstituted        S(O)_(n)C₁-C₆ alkyl, substituted or unsubstituted        N(C₁-C₆alkyl)₂, wherein each said substituted alkyl, substituted        alkenyl, substituted alkoxy, substituted alkenyloxy, substituted        cycloalkyl, substituted cycloalkenyl, substituted aryl,        substituted heterocyclyl, has one or more substituents        independently selected from F, Cl, Br, I, CN, NO₂, C₁-C₆ alkyl,        C₂-C₆ alkenyl, C₁-C₆ haloalkyl, C₂-C₆ haloalkenyl, C₁-C₆        haloalkyloxy, C₂-C₆ haloalkenyloxy, C₃-C₁₀ cycloalkyl, C₃-C₁₀        cycloalkenyl, C₃-C₁₀ halocycloalkyl, C₃-C₁₀ halocycloalkenyl,        OC₁-C₆ alkyl, OC₁-C₆ haloalkyl, S(O)_(n)C₁-C₆alkyl,        S(O)_(n)OC₁-C₆ alkyl, C₆-C₂₀ aryl, or C₁-C₂₀ heterocyclyl, C₂-C₆        alkynyl, C₁-C₆ alkoxy, N(R9)S(O)_(n)R9, OR9, N(R9)₂, R9OR9,        R9N(R9)₂, R9C(=X1)R9, R9C(=X1)N(R9)₂, N(R9)C(=X1)R9,        R9N(R9)C(=X1)R9, S(O)_(n)OR9, R9C(=X1)OR9, R9OC(=X1)R9,        R9S(O)_(n)R9, S(O)_(n)R9, oxo, (each of which that can be        substituted, may optionally be substituted with R9);

(j) R9 is (each independently) H, CN, substituted or unsubstituted C₁-C₆alkyl, substituted or unsubstituted C₂-C₆ alkenyl, substituted orunsubstituted C₁-C₆ alkoxy, substituted or unsubstituted C₂-C₆alkenyloxy, substituted or unsubstituted C₃-C₁₀ cycloalkyl, substitutedor unsubstituted C₃-C₁₀ cycloalkenyl, substituted or unsubstitutedC₆-C₂₀ aryl, substituted or unsubstituted C₁-C₂₀ heterocyclyl,substituted or unsubstituted S(O)_(n)C₁-C₆ alkyl, substituted orunsubstituted N(C₁-C₆alkyl)₂,

-   -   wherein each said R9, which is substituted, has one or more        substituents selected from F, Cl, Br, I, CN, NO₂, C₁-C₆ alkyl,        C₂-C₆ alkenyl, C₁-C₆ haloalkyl, C₂-C₆ haloalkenyl, C₁-C₆        haloalkyloxy, C₂-C₆ haloalkenyloxy, C₃-C₁₀ cycloalkyl, C₃-C₁₀        cycloalkenyl, C₃-C₁₀ halocycloalkyl, C₃-C₁₀ halocycloalkenyl,        OC₁-C₆ alkyl, OC₁-C₆ haloalkyl, S(O)_(n)C₁-C₆alkyl,        S(O)_(n)OC₁-C₆ alkyl, C₆-C₂₀ aryl, or C₁-C₂₀ heterocyclyl;

(k) n is 0, 1, or 2;

(l) X is N or CR_(n1) where R_(n1) is H, F, Cl, Br, I, CN, NO₂,substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstitutedC₂-C₆ alkenyl, substituted or unsubstituted C₁-C₆ alkoxy, substituted orunsubstituted C₂-C₆ alkenyloxy, substituted or unsubstituted C₃-C₁₀cycloalkyl, substituted or unsubstituted C₃-C₁₀ cycloalkenyl,substituted or unsubstituted C₆-C₂₀ aryl, substituted or unsubstitutedC₁-C₂₀ heterocyclyl, OR9, C(=X1)R9, C(=X1)OR9, C(=X1)N(R9)₂, N(R9)₂,N(R9)C(=X1)R9, SR9, S(O)_(n)R9, S(O)_(n)OR9, or R9S(O)_(n)R9,

-   -   wherein each said R_(n1) which is substituted, has one or more        substituents selected from F, Cl, Br, I, CN, NO₂, C₁-C₆ alkyl,        C₂-C₆ alkenyl, C₁-C₆ haloalkyl, C₂-C₆ haloalkenyl, C₁-C₆        haloalkyloxy, C₂-C₆ haloalkenyloxy, C₃-C₁₀ cycloalkyl, C₃-C₁₀        cycloalkenyl, C₃-C₁₀ halocycloalkyl, C₃-C₁₀ halocycloalkenyl,        OR9, S(O)_(n)OR9, C₆-C₂₀ aryl, or C₁-C₂₀ heterocyclyl, (each of        which that can be substituted, may optionally be substituted        with R9);

(m) X1 is (each independently) O or S;

(n) X2 is (each independently) O, S, =NR9, or =NOR9;

(o) Z is CN, NO₂, C₁-C₆ alkyl(R9), C(=X1)N(R9)₂;

(p) R11 is Q₁(C≡C)R12, wherein Q₁ is a bond, substituted orunsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₂-C₆ alkenyl,substituted or unsubstituted C₂-C₆ alkynyl, substituted or unsubstitutedC₃-C₁₀ cycloalkyl, substituted or unsubstituted C₂-C₁₀ cycloalkoxy,substituted or unsubstituted C₁-C₆ alkylOR9, substituted orunsubstituted C₁-C₆ alkylS(O)_(n)R9, substituted or unsubstituted C₁-C₆alkylS(O)_(n)(=NR9), substituted or unsubstituted C₁-C₆ alkylN(R9)(where (C≡C) is attached directly to the N by a bond), substituted orunsubstituted C₁-C₆ alkylN(R9)₂, substituted or unsubstituted C₂-C₆alkenyloxy, substituted or unsubstituted C₃-C₁₀ cycloalkenyl,substituted or unsubstituted C₀-C₆ alkylC(=R7)C₀-C₆ alkylR9, substitutedor unsubstituted C₀-C₆ alkylC(=R7)OR9, substituted or unsubstitutedC₁-C₆ alkylOC₀-C₆ alkylC(=R7)R9, substituted or unsubstituted C₁-C₆alkylN(R9)(C(=R7)R9), substituted or unsubstituted C₁-C₆alkylN(R9)(C(=R7)OR9), substituted or unsubstituted C₀-C₆ alkylC(=R7)C₀-C₆ alkylN(R9) (where (C≡C) is attached directly to the N by abond), substituted or unsubstituted C₀-C₆alkylC(=R7)C₀-C₆ alkylN(R9)₂,OR9, S(O)_(n)R9, N(R9)R9, substituted or unsubstituted C₆-C₂₀ aryl,substituted or unsubstituted C₁-C₂₀ heterocyclyl,

-   -   wherein each said Q₁, which is substituted, has one or more        substituents selected from F, Cl, Br, I, CN, NO₂, C₁-C₆ alkyl,        C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ haloalkyl, C₂-C₆        haloalkenyl, C₁-C₆ haloalkyloxy, C₂-C₆ haloalkenyloxy, C₃-C₁₀        cycloalkyl, C₃-C₁₀ cycloalkenyl, C₃-C₁₀ halocycloalkyl, C₃-C₁₀        halocycloalkenyl, OR9, SR9, S(O)_(n)R9, S(O)_(n)OR9, C₆-C₂₀        aryl, or C₁-C₂₀ heterocyclyl, R9aryl, C₁-C₆alkylOR9,        C₁-C₆alkylS(O)_(n)R9, (each of which that can be substituted,        may optionally be substituted with R9)    -   optionally Q₁ and R8 can be connected in a cyclic arrangement,        where optionally such arrangement can have one or more        heteroatoms selected from O, S, or N, in the cyclic structure        connecting Q₁ and R8;

(q) R12 is Q₁ (except where Q₁ is a bond), F, Cl, Br, I, Si(R9)₃ (whereeach R9 is independently selected), or R9; and

(r) with the following provisos

-   -   (1) that R6 and R8 cannot both be C(═O)CH₃,    -   (2) that when A1 is A11 then R6 and R8 together do not form        fused ring systems,    -   (3) that R6 and R8 are not linked in a cyclic arrangement with        only —CH₂—,    -   (4) that when A is A2 then R5 is not C(═O)OH,    -   (5) that when A is A2 and R6 is H then R8 is not a —(C₁-C₆        alkyl)-O—(substituted aryl), and    -   (6) that when A is A2 then R6 is not —(C₁alkyl)(substituted        aryl).

In another embodiment of this invention A is A1.

In another embodiment of this invention A is A2.

In another embodiment of this invention R1 is H.

In another embodiment of this invention R2 is H.

In another embodiment of this invention R3 is selected from H, orsubstituted or unsubstituted C₁-C₆ alkyl.

In another embodiment of this invention R3 is selected from H or CH₃.

In another embodiment of the invention when A is A1 then A1 is A11.

In another embodiment of the invention when A is A1, and A1 is A11, thenR4 is selected from H, or substituted or unsubstituted C₁-C₆ alkyl, orsubstituted or unsubstituted C₆-C₂₀ aryl.

In another embodiment of the invention when A is A1, and A1 is A11 thenR4 is selected from CH₃, CH(CH₃)₂, or phenyl.

In another embodiment of the invention when A is A1, and A1 is A12, thenR4 is CH₃.

In another embodiment of this invention when A is A2 then R4 is selectedfrom H, or substituted or unsubstituted C₁-C₆ alkyl, substituted orunsubstituted C₂-C₆ alkenyl, substituted or unsubstituted C₃-C₁₀cycloalkyl, substituted or unsubstituted C₆-C₂₀ aryl, wherein each saidR4, which is substituted, has one or more substituents selected from F,Cl, Br, or I.

In another embodiment of this invention when A is A2 then R4 is H orC₁-C₆ alkyl.

In another embodiment of this invention when A is A2 then R4 is H, CH₃,CH₂CH₃, CH═CH₂, cyclopropyl, CH₂Cl, CF₃, or phenyl.

In another embodiment of this invention when A is A2 then R4 is Br orCl.

In another embodiment of this invention R5 is H, F, Cl, Br, I, orsubstituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstitutedC₁-C₆ alkoxy.

In another embodiment of this invention R5 is H, OCH₂CH₃, F, Cl, Br, orCH₃.

In another embodiment of this invention, when A is A1 then R6 issubstituted or unsubstituted C₁-C₆ alkyl.

In another embodiment of this invention when A is A2 then R6 is selectedfrom is substituted or unsubstituted C₁-C₆ alkyl, substituted orunsubstituted C₂-C₆ alkenyl, substituted or unsubstituted C₃-C₁₀cycloalkyl, C(=X1)R9, C(=X1)X2R9, R9X2R9, C(═O)(C₁-C₆alkyl)S(O)_(n)(C₁-C₆ alkyl), (C₁-C₆ alkyl)OC(═O)(C₆-C₂₀ aryl), (C₁-C₆alkyl)OC(═O)(C₁-C₆ alkyl), or R9X2C(=X1)X2R9.

In another embodiment of this invention when A is A2 then R6 and R8 areconnected in a cyclic arrangement, where optionally such arrangement canhave one or more heteroatoms selected from O, S, or, N, in the cyclicstructure connecting R6 and R8.

In another embodiment of this invention R6 is C₁-C₆ alkyl, or C₁-C₆alkyl-phenyl.

In another embodiment of this invention R6 is H, CH₃, CH₂CH₃, CH₂CH₂CH₃,CH(CH₃)₂, CH₂phenyl, CH₂CH(CH₃)₂, CH₂cyclopropyl, C(═O)CH₂CH₂SCH₃,C(═O)OC(CH₃)₃, CH₂CH═CH₂, C(═O)OCH₂CH₃, C(═O)CH(CH₃)CH₂SCH₃,cyclopropyl, CD₃, CH₂OC(═O)phenyl, C(═O)CH₃, C(═O)CH(CH₃)₂,CH₂OC(═O)CH(CH₃)₂, CH₂OC(═O)CH₃, C(═O)phenyl, CH₂OCH₃,CH₂OC(═O)CH₂OCH₂CH₃, CH₂CH₂OCH₃, CH₂OC(═O)OCH(CH₃)₂, CH₂CH₂OCH₂OCH₃,CH₂CH₂OCH₃, CH₂CH₂OC(═O)CH₃, CH₂CN.

In another embodiment of this invention R6 is methyl or ethyl.

In another embodiment of this invention R7 is O or S.

In another embodiment of this invention R8 is selected from substitutedor unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₂-C₆alkenyl, substituted or unsubstituted C₃-C₁₀ cycloalkyl, substituted orunsubstituted C₆-C₂₀ aryl, substituted or unsubstituted C₁-C₂₀heterocyclyl, R9C(=X1)OR9, SR9, S(O)_(n)OR9, R9S(O)_(n)R9, orR9S(O)_(n)(NZ)R9.

In another embodiment of this invention R8 is CH(CH₃)CH₂SCH₃, CH(CH₃)₂,C(CH₃)₂CH₂SCH₃, CH₂CH₂SCH₃, CH₂CF₃, CH₂CH₂C(═O)OCH₃, N(H)(CH₂CH₂SCH₃),OCH₂CH₂SCH₃, CH(CH₂SCH₃)(CH₂phenyl), thiazolyl, oxazolyl, isothiazolyl,substituted-furanyl, CH₃, C(CH₃)₃, phenyl, CH₂CH₂OCH₃, pyridyl,CH₂CH(CH₃)SCH₃, OC(CH₃)₃, C(CH₃)₂CH₂SCH₃, CH(CH₃)CH(CH₃)SCH₃,CH(CH₃)CF₃, CH₂CH₂-thienyl, CH(CH₃)SCF₃, CH₂CH₂Cl, CH₂CH₂CH₂CF₃,CH₂CH₂S(═O)CH₃, CH(CH₃)CH₂S(═O)CH₃, CH₂CH₂S(═O)₂CH₃,CH(CH₃)CH₂S(═O)₂CH₃, NCH₂CH₃, N(H)(CH₂CH₂CH₃), C(CH₃)═C(H)(CH₃),N(H)(CH₂CH═CH₂), CH₂CH(CF₃)SCH₃, CH(CF₃)CH₂SCH₃, thietanyl, CH₂CH(CF₃)₂,CH₂CH₂CF(OCF₃)CF₃, CH₂CH₂CF(CF₃)CF₃, CF(CH₃)₂, CH(CH₃)phenyl-Cl,CH(CH₃)phenyl-F, CH(CH₃)phenyl-OCF₃, CH₂N(CH₃)(S(═O)₂N(CH₃)₂,CH(CH₃)OCH₂CH₂SCH₃, CH(CH₃)OCH₂CH₂OCH₃, OCH₃, CH(CH₃)SCH₃, CH₂SCH₃,N(H)CH₃, CH(Br)CH₂Br, or CH(CH₃)CH₂SCD₃.

In another more preferred embodiment of this invention R8 is preferablyR13-S(O)_(n)—R13 wherein each R13 is independently selected fromsubstituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstitutedC₂-C₆ alkenyl, substituted or unsubstituted C₁-C₆ alkoxy, substituted orunsubstituted C₂-C₆ alkenyloxy, substituted or unsubstituted C₃-C₁₀cycloalkyl, substituted or unsubstituted C₃-C₁₀ cycloalkenyl,substituted or unsubstituted C₆-C₂₀ aryl, substituted or unsubstitutedC₁-C₂₀ heterocyclyl, substituted or unsubstituted S(O)_(n)C₁-C₆ alkyl,substituted or unsubstituted N(C₁-C₆alkyl)₂, wherein each saidsubstituted alkyl, substituted alkenyl, substituted alkoxy, substitutedalkenyloxy, substituted cycloalkyl, substituted cycloalkenyl,substituted aryl, substituted heterocyclyl, has one or more substituentsindependently selected from F, Cl, Br, I, CN, NO₂, C₁-C₆ alkyl, C₂-C₆alkenyl, C₁-C₆ haloalkyl, C₂-C₆ haloalkenyl, C₁-C₆ haloalkyloxy, C₂-C₆haloalkenyloxy, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkenyl, C₃-C₁₀halocycloalkyl, C₃-C₁₀ halocycloalkenyl, OC₁-C₆ alkyl, OC₁-C₆ haloalkyl,S(O)_(n)C₁-C₆alkyl, S(O)_(n)OC₁-C₆ alkyl, C₆-C₂₀ aryl, or C₁-C₂₀heterocyclyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, N(R9)S(O)_(n)R9, OR9, N(R9)₂,R9OR9, R9N(R9)₂, R9C(=X1)R9, R9C(=X1)N(R9)₂, N(R9)C(=X1)R9,R9N(R9)C(=X1)R9, S(O)_(n)OR9, R9C(=X1)OR9, R9OC(=X1)R9, R9S(O)_(n)R9,S(O)_(n)R9, oxo, (each of which that can be substituted, may optionallybe substituted with R9).

In another embodiment of this invention R8 is (substituted orunsubstituted C₁-C₆ alkyl)-S(O)_(n)-(substituted or unsubstituted C₁-C₆alkyl) wherein said substituents on said substituted alkyls areindependently selected from F, Cl, Br, I, CN, NO₂, C₁-C₆ alkyl, C₂-C₆alkenyl, C₁-C₆ haloalkyl, C₂-C₆ haloalkenyl, C₁-C₆ haloalkyloxy, C₂-C₆haloalkenyloxy, C₃-C₁₀cycloalkyl, C₃-C₁₀ cycloalkenyl, C₃-C₁₀halocycloalkyl, C₃-C₁₀ halocycloalkenyl, OC₁-C₆ alkyl, OC₁-C₆ haloalkyl,S(O)_(n)C₁-C₆alkyl, S(O)_(n)OC₁-C₆ alkyl, C₆-C₂₀ aryl, or C₁-C₂₀heterocyclyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, N(R9)S(O)_(n)R9, OR9, N(R9)₂,R9OR9, R9N(R9)₂, R9C(=X1)R9, R9C(=X1)N(R9)₂, N(R9)C(=X1)R9,R9N(R9)C(=X1)R9, S(O)_(n)OR9, R9C(=X1)OR9, R9OC(=X1)R9, R9S(O)_(n)R9,S(O)_(n)R9, oxo, (each of which that can be substituted, may optionallybe substituted with R9).

In another embodiment of this invention R8 is selected fromCH(CH₃)SCH₂CF₃, CH₂CH₂SCH₂CF₃, CH₂SCH₂CF₃, CH₂SCHClCF₃,CH(CH₂CH₃)SCH₂CF₃, CH(CH₃)SCH₂CHF₂, CH(CH₃)SCH₂CH₂F, CH₂CH₂SCH₂CH₂F,CH(CH₃)S(═O)₂CH₂CF₃, CH(CH₃)S(═O)CH₂CF₃, CH(CH₃)CH₂SCF₃, CH(CH₃)CH₂SCF₃,CH(CH₃)SCH₂CH₂CF₃, and CH₂CH₂SCH₂CH₂CF₃.

In another embodiment of this invention R8 is (substituted orunsubstituted C₁-C₆ alkyl)-S(O)_(n)-(substituted or unsubstituted C₁-C₆alkyl)-(substituted or unsubstituted C₃-C₁₀ cycloalkyl) wherein saidsubstituents on said substituted alkyls and said substituted cycloalkylsare independently selected from F, Cl, Br, I, CN, NO₂, C₁-C₆ alkyl,C₂-C₆ alkenyl, C₁-C₆ haloalkyl, C₂-C₆ haloalkenyl, C₁-C₆ haloalkyloxy,C₂-C₆ haloalkenyloxy, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkenyl, C₃-C₁₀halocycloalkyl, C₃-C₁₀ halocycloalkenyl, OC₁-C₆ alkyl, OC₁-C₆ haloalkyl,S(O)_(n)C₁-C₆alkyl, S(O)_(n)OC₁-C₆ alkyl, C₆-C₂₀ aryl, or C₁-C₂₀heterocyclyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, N(R9)S(O)_(n)R9, OR9, N(R9)₂,R9OR9, R9N(R9)₂, R9C(=X1)R9, R9C(=X1)N(R9)₂, N(R9)C(=X1)R9,R9N(R9)C(=X1)R9, S(O)_(n)OR9, R9C(=X1)OR9, R9OC(=X1)R9, R9S(O)_(n)R9,S(O)_(n)R9, oxo, (each of which that can be substituted, may optionallybe substituted with R9).

In another embodiment of this invention R8 is selected fromCH(CH₃)CH₂SCH₂(2,2 difluorocyclopropyl), CH₂CH₂SCH₂(2,2difluorocyclopropyl), CH₂CH₂S(═O)CH₂(2,2 difluorocyclopropyl),CH₂CH₂S(═O)₂ CH₂CH₂(2,2 difluorocyclopropyl), and CH₂CH(CF₃)SCH₂(2,2difluorocyclopropyl).

In another embodiment of this invention R8 is (substituted orunsubstituted C₁-C₆ alkyl)-S(O)_(n)-(substituted or unsubstituted C₂-C₆alkenyl) wherein said substituents on said substituted alkyls andsubstituted alkenyls are independently selected from F, Cl, Br, I, CN,NO₂, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₁-C₆ haloalkyl, C₂-C₆ haloalkenyl,C₁-C₆ haloalkyloxy, C₂-C₆ haloalkenyloxy, C₃-C₁₀ cycloalkyl, C₃-C₁₀cycloalkenyl, C₃-C₁₀ halocycloalkyl, C₃-C₁₀ halocycloalkenyl, OC₁-C₆alkyl, OC₁-C₆ haloalkyl, S(O)_(n)C₁-C₆alkyl, S(O)_(n)OC₁-C₆ alkyl,C₆-C₂₀ aryl, or C₁-C₂₀ heterocyclyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy,N(R9)S(O)_(n)R9, OR9, N(R9)₂, R9OR9, R9N(R9)₂, R9C(=X1)R9,R9C(=X1)N(R9)₂, N(R9)C(=X1)R9, R9N(R9)C(=X1)R9, S(O)_(n)OR9,R9C(=X1)OR9, R9OC(=X1)R9, R9S(O)_(n)R9, S(O)_(n)R9, oxo, (each of whichthat can be substituted, may optionally be substituted with R9).

In another embodiment of this invention R8 is selected fromCH₂CH₂SCH₂CH═CCl₂, CH2SCH2CH═CCl₂, CH(CH3)SCH2CH═CCl₂, CH(CH3)SCH═CHF,CH₂CH₂S(═O)CH₂CH₂CF₃, and CH₂CH₂S(═O)₂CH₂CH₂CF₃.

In another embodiment of this invention X is CR_(n1) where R_(n1) is Hor halo.

In another embodiment of this invention X is CR_(n1) where R_(n1) is Hor F.

In another embodiment of this invention X1 is O.

In another embodiment of this invention X2 is O.

In another embodiment of this invention R11 is substituted orunsubstituted C₁-C₆ alkylC≡CR12.

In another embodiment of this invention R11 is CH₂C≡CH.

The molecules of Formula One will generally have a molecular mass ofabout 100 Daltons to about 1200 Daltons. However, it is generallypreferred if the molecular mass is from about 120 Daltons to about 900Daltons, and it is even more generally preferred if the molecular massis from about 140 Daltons to about 600 Daltons.

The following schemes illustrate approaches to generatingaminopyrazoles. In step a of Scheme I, treatment of a 3-acetopyridine ora 5-acetopyrimidine of Formula II, wherein R1, R2, R3 and X are aspreviously defined, with carbon disulfide and iodomethane in thepresence of a base such as sodium hydride and in a solvent such asdimethyl sulfoxide provides the compound of Formula III. In step b ofScheme I, the compound of Formula III can be treated with an amine oramine hydrochloride, in the presence of a base, such as triethylamine,in a solvent such as ethyl alcohol to afford the compound of Formula IV,wherein R1, R2, R3, R6 and X are as previously defined. The compound ofFormula IV can be transformed into the aminopyrazole of Formula Va whereR5=H as in step c of Scheme I and as in Peruncheralathan, S. et al. J.Org. Chem. 2005, 70, 9644-9647, by reaction with a hydrazine, such asmethylhydrazine, in a polar protic solvent such as ethyl alcohol.

Another approach to aminopyrazoles is illustrated in Scheme II. In stepa, the nitrile of Formula VI wherein X, R1, R2 and R3 are as previouslydefined and R5 is hydrogen, is condensed as in Dhananjay, B. Kendre etal. J. Het Chem 2008, 45, (5), 1281-86 with hydrazine of Formula VII,such as methylhydrazine to give a mixture of aminopyrazoles of FormulaVb, wherein R5 and R6=H, both of whose components were isolated.

Preparation of aminopyrazoles such as those of Formula XIIa isdemonstrated in Scheme III. The compound of Formula X in step a and asin Cristau, Henri-Jean et al. Eur. J. Org. Chem. 2004, 695-709 can beprepared through the N-arylation of a pyrazole of Formula IX with anappropriate aryl halide of Formula VIIIa where Q is bromo in thepresence of a base such as cesium carbonate, a copper catalyst such ascopper (II) oxide and a ligand such as salicylaldoxime in a polaraprotic solvent such as acetonitrile. Compounds of Formula IX, as shownin Scheme III, wherein R4=Cl and R5=H, can be prepared as in Pelcman, B.et al WO 2007/045868 A1. Nitration of the pyridylpyrazole of Formula Xas in step b of Scheme III and as in Khan, Misbanul Ain et al. J.Heterocyclic Chem. 1981, 18, 9-14 by reaction with nitric acid andsulfuric acid gave compounds of Formula XIa. Reduction of the nitrofunctionality of compounds of Formula XIa in the presence of hydrogenwith a catalyst such as 5% Pd/C in a polar aprotic solvent such astetrahydrofuran gave the amine of Formula XIIa, as shown in step c inScheme III. Reduction of the nitro functionality of compounds of FormulaXIa, wherein R1, R2, R3, R4 and X are as previously defined and R5=H, inthe presence of hydrogen with a catalyst such as 10% Pd/C in a polarprotic solvent such as ethanol gave the amine of Formula XIIa, whereinR5=H, as well as the amine of Formula XIIa, wherein R5=OEt, as shown instep d of Scheme III. Compounds of Formula XIa, wherein R1, R2, R3, R5and X are as previously defined and R4=Cl, can be reduced in thepresence of a reducing agent such as iron in a mixture of polar proticsolvents such as acetic acid, water, and ethanol to give amines ofFormula XIIa, wherein R1, R2, R3, R5 and X are as previously definedR4=Cl, as shown in step e of Scheme III. Compounds of Formula XIa,wherein R1, R2, R3, R5 and X are as previously defined and R4=Cl, can beallowed to react under Suzuki coupling conditions with a boronic acidsuch as phenylboronic acid in the presence of a catalyst such aspalladium tetrakis, a base such as 2M aqueous potassium carbonate, andin a mixed solvent system such as ethanol and toluene to providecross-coupled pyrazoles of Formula XIb, as shown in step f of SchemeIII.

In step a of Scheme IV, the compounds of Formula XIIb can be treatedwith triethylorthoformate and an acid such as trifluoroacetic acid.Subsequent addition of a reducing agent such as sodium borohydride in apolar protic solvent such as ethanol gave a compound of Formula XIIIa,wherein R6=methyl.

In step b of Scheme IV, the compound of Formula XIIb can be treated withacetone in a solvent such as isopropyl acetate, an acid such astrifluoroacetic acid and sodium triacetoxyborohydride to give compoundsof Formula XIIIa, wherein R6=isopropyl.

In step c of Scheme IV, the compounds of Formula XIIb can be acylatedwith an acid chloride such as acetyl chloride in a polar aprotic solventsuch as dichloromethane using the conditions described in Scheme V.Reduction of the amide with a reducing agent such as lithium aluminumhydride in a polar aprotic solvent such tetrahydrofuran gives compoundsof Formula XIIIa, wherein R6=ethyl.

Alternatively, in step d of Scheme IV, the compounds of Formula XIIb canbe treated with benzotriazole and an aldehyde in ethanol followed byreduction using, for example, sodium borohydride, to afford compounds ofFormula XIIIa. In step e of Scheme IV, the compounds of Formula XIIb canbe treated with an aldehyde such as propionaldehyde and sodiumtriacetoxyborohydride in a polar aprotic solvent such as dichloromethaneto give compounds of Formula XIIIa, wherein R6=propyl. As in step f,acylation of compounds of Formula XIIIa in Scheme IV using theconditions described in Scheme IX affords compounds of Formula Ia,wherein R1, R2, R3, R4, R5, R6, R8 and X are as previously defined.

In step a of Scheme V, the compounds of Formula Vc, wherein R1, R2, R3,R4, R5 and R6 and X are as previously defined, can be treated with anacid chloride of Formula XIV, in the presence of a base such astriethylamine or N,N-dimethylaminopyridine in a polar aprotic solventsuch as dichloroethane (DCE) to yield compounds of Formula Ib, whereinR8 is as previously defined. Additionally, when R6=H the 2° amide may besubsequently alkylated in step b of Scheme V with an alkyl halide suchas iodoethane, in the presence of a base such as sodium hydride and apolar aprotic solvent such as N,N-dimethylformamide (DMF) to yield thedesired compounds of Formula Ib. The acid chlorides used in theacylation reactions herein are either commercially available or can besynthesized by those skilled in the art.

In step a of Scheme VI and as in Sammelson et al. Bioorg. Med. Chem.2004, 12, 3345-3355, the aminopyrazoles of Formula Vd, wherein R1, R2,R3, R4, R6 and X are as previously defined and R5=H, can be halogenatedwith a halogen source such as N-chlorosuccinimide or N-bromosuccinimidein a polar aprotic solvent such as acetonitrile to provide theR5-substituted pyrazole. In step b, acylation of this compound using theconditions described in Scheme V affords the compound of Formula Ic,wherein R1, R2, R3, R4, R5, R6, R8 and X are as previously defined.

In step a of Scheme VII, ureas and carbamates are made from theaminopyrazoles of Formula Ve. Compounds of Formula Ve, wherein X, R1,R2, R3, R4, R5 and R6 are as previously defined are allowed to reactwith phosgene to provide the intermediate carbamoyl chloride which issubsequently treated with an amine, as shown in step b, or alcohol, asshown in step c, respectively, to generate a urea of Formula Id or acarbamate of Formula Ie, respectively, wherein R9 is as previouslydefined.

In step a of Scheme VIII, compounds of Formula XIIc, wherein X, R1, R2,R3, R4 and R5 are as previously defined, can be treated withdi-tert-butyl dicarbonate (Boc₂O) and a base such as triethylamine in apolar aprotic solvent such as dichloromethane (DCM) to yield compoundsof Formula XVIa. Treatment of the carbamate functionality with an alkylhalide such as iodomethane or Boc-anhydride in the presence of a basesuch as sodium hydride and in a polar aprotic solvent such as DMF yieldscarbamates of Formula XVII, as shown in step b of Scheme VIII, whereinR6 is as previously defined, except where R6 is hydrogen. The Boc-groupcan be removed under conditions that are well-known in the art, such asunder acidic conditions such as trifluoroacetic acid (TFA) in a polaraprotic solvent like dichloromethane to give compounds of Formula XIIIbas in step c.

In steps a, b and c of Scheme IX, compounds of Formula XIIIc, wherein X,R1, R2, R3, R4, R5 and R6 are as previously defined, can be treated witha compound of Formula XVIII, wherein R8 is as previously defined and R10is either OH, OR9 or O(C═O)OR9, to yield compounds of Formula Id. WhenR10=OH, compounds of Formula XIIIc can be converted to compounds ofFormula Id in the presence of a coupling reagent such as1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC.HCl)and a base such as N,N-dimethylaminopyridine (DMAP) in a polar aproticsolvent such as dichloroethane (DCE), as shown in step a. When R10=OR9,compounds of Formula XIIIc can be converted to compounds of Formula Idin the presence of 2,3,4,6,7,8-hexahydro-1H-pyrimido[1,2-a]pyrimidine ina polar aprotic solvent such as 1,4-dioxane under elevated temperature,as shown in step b. When R10=O(C═O)OR9, compounds of Formula XIIIc canbe converted to compounds of Formula Id in a polar aprotic solvent suchas dichloromethane (DCM), as shown in step c. Acylation of amides ofFormula Id, when R6=H, with an acid chloride in the presence of a basesuch as diisopropyl ethylamine in a polar aprotic solvent such asdichloroethane (DCE) yields imides of Formula Ie, as shown in step d.Furthermore, alkylation of amides of Formula Id, when R6=H, with analkyl halide or alkyl sulfonate in the presence of a base such as sodiumhydride in a polar aprotic solvent such as N,N-dimethylformamide (DMF)yields alkylated amides of Formula Ie, as shown in step e. Halogenationof compounds of Formula Id, wherein R1, R2, R3, R4, R6, R8 and X are aspreviously defined and R5=H, with a halogen source such asN-bromosuccinimide in a polar aprotic solvent such as DCE or a halogensource such as N-chlorosuccinimide in a polar aprotic solvent such asDCE or acetonitrile or a halogen source such as Selectfluor® in amixture of polar aprotic solvents such as acetonitrile and DMF givehalogenated pyrazoles of Formula Ie, wherein R5=halogen, as shown instep f of Scheme IX. Amides of Formula Id can be converted to thioamidesof Formula If in the presence of a thionating agent such as Lawesson'sreagent in a polar aprotic solvent such as dichloroethane (DCE), asshown in step g.

In step a of Scheme X, compounds of Formula XIIId, wherein X, R1, R2,R3, R4, R5 and R6 are as previously defined, can be treated withcompounds of Formula XIX, wherein R8 is as previously defined, in apolar aprotic solvent such as dichloroethane (DCE) to yield compounds ofFormula XX. Additionally, when R6=H and R8 contains a halogen, compoundsof Formula XX can be treated with a base, such as sodium hydride, in apolar aprotic solvent, such as THF, to yield compounds of Formula XXI,where m is an integer selected from 1, 2, 3, 4, 5, or 6, as shown instep b of Scheme X.

Oxidation of the sulfide to the sulfoxide or sulfone is accomplished asin Scheme XI where (˜S˜) can be any sulfide previously defined withinthe scope of R8 of this invention. The sulfide of Formula XXIIa, whereinX, R1, R2, R3, R4, R5 and R6 are as previously defined, is treated withan oxidant such as sodium perborate tetrahydrate in a polar proticsolvent such as glacial acetic acid to give the sulfoxide of FormulaXXIII as in step a of Scheme XI. Alternatively, the sulfide of FormulaXXIIa can be oxidized with an oxidant such as hydrogen peroxide in apolar protic solvent such as hexafluoroisopropanol to give the sulfoxideof Formula XXIII as in step d of Scheme XI. The sulfoxide of FormulaXXIII can be further oxidized to the sulfone of Formula XXIV by sodiumperborate tetrahydrate in a polar protic solvent such as glacial aceticacid as in step c of Scheme XI. Alternatively, the sulfone of FormulaXXIV can be generated in a one-step procedure from the sulfide ofFormula XXIIa by using the aforementioned conditions with >2 equivalentsof sodium perborate tetrahydrate, as in step b of Scheme XI.

Oxidation of the sulfide to the sulfoximine is accomplished as in SchemeXII where (˜S˜) can be any sulfide previously defined within the scopeof R8 of this invention. The sulfide of Formula XXIIb, wherein X, R1,R2, R3, R4, R5 and R6 are as previously defined, is oxidized as in stepa with iodobenzene diacetate in the presence of cyanamide in a polaraprotic solvent such as methylene chloride (DCM) to give the sulfilimineof the Formula XXV. The sulfilimine of Formula XXV may be furtheroxidized to the sulfoximine of Formula XXVI with an oxidant such asmeta-Chloroperoxybenzoic acid (“mCPBA”) in the presence of a base suchas potassium carbonate in a protic polar solvent system such as ethanoland water as in step b of Scheme XII.

Iodination of the pyrazole of Formula Xb as in step a of Scheme XIII andas in Potapov, A. et al. Russ. J. Org. Chem. 2006, 42, 1368-1373 wasaccomplished by reaction with an iodinating agent such as iodine in thepresence of acids such as iodic acid and sulfuric acid in a polar proticsolvent such as acetic acid gives compounds of Formula XXVII. In step bof Scheme XIII and as in Wang, D. et al. Adv. Synth. Catal. 2009, 351,1722-1726, aminopyrazoles of Formula XIIIe can be prepared fromiodopyrazoles of Formula XXVII through cross coupling reactions with anappropriate amine in the presence of a base such as cesium carbonate, acopper catalyst such as copper (I) bromide, and a ligand such as1-(5,6,7,8-tetrahydroquinolin-8-yl)ethanone in a polar aprotic solventsuch as DMSO.

In step a of the Scheme XIV, compounds of the formula XXIX, wherein R4is Cl, R5 is H and X⁻ represents Cl⁻, can be prepared according to themethods described in Acta. Pharm. Suec. 22, 147-156 (1985) by Tolf,Bo-Ragnar and Dahlbom, R. In a similar manner, compounds of the FormulaXXIX, wherein R4 is Br, X⁻ represents Br and R5 is as definedpreviously, can be prepared by treating compounds of the Formula XXVIIIwith hydrogen gas in the presence of a metal catalyst such as 5% Pd onalumina and a solution of 50% aqueous HBr in a solvent such as ethanol.Alternatively, in step a of Scheme XIV, compounds of the Formula XXIX,wherein R4 is Cl or Br, X⁻ represents Cl⁻ or Br and R5 is as definedpreviously, can be prepared by treating compounds of the Formula XXVIII,wherein R5 is as defined previously, with a hydrosilane such as triethylsilane in the presence of a metal catalyst such as 5% Pd on alumina andan acid such as HCl or HBr, respectively, in a solvent such as ethanol.

In step b of the Scheme XIV, compounds of the Formula XXX, wherein R4 isCl or Br and R5 is as defined previously, can be prepared by treatingthe compounds of the Formula XXIX, wherein R4 is Cl or Br, X⁻ representsCl⁻ or Br and R5 is as defined previously, with di-tert-butyldicarbonate (Boc₂O) in the presence of a mixture of solvents such as THFand water and a base such as sodium bicarbonate.

In step c of the Scheme XIV, compounds of the Formula XVIa, wherein X,R1, R2, R3 and R5 are as defined previously and R4 is Cl or Br,preferably Cl can be obtained by treating compounds of the Formula XXX,wherein R4 is Cl or Br and R5 is as defined previously, preferably H,with compounds of the Formula VIIIb, wherein X, R1, R2 and R3 are asdefined previously and Q is iodo, in the presence of a catalytic amountof copper salt such as CuCl₂, a ligand such as an ethane-1,2-diaminederivative such as N¹,N²-dimethylethane-1,2-diamine and a base such asK₃PO₄ in a polar aprotic solvent such as acetonitrile at a suitabletemperature.

In step c pyrazoles of Formula XXX are coupled with compounds of theFormula VIIIb, preferably 3-iodo pyridine, in the presence of a metalcatalyst, such as CuCl₂, and a diamine ligand such asN¹,N²-dimethylethane-1,2-diamine, and an inorganic base, such as K₃PO₄.The reaction is carried out in a polar aprotic solvent such asacetonitrile. The reaction is conducted at a temperature from about 60°C. to about 82° C. and preferably from about 75° C. to 82° C.Approximately, a 1:1.2 molar ratio of pyrazoles of Formula XXX toheterocyclyl iodide of Formula VIIIb may be used, however, a molarratios of about 5:1 to about 1:5 may also be used. The reaction isconducted at about atmospheric pressure, however, higher or lowerpressures can be used.

The Boc-group of compounds of Formula XVIa can be removed underconditions that are well-known in the art such as under acidicconditions such as TFA in a polar aprotic solvent such asdichloromethane to give compounds of Formula XIId, as shown in step d ofScheme XIV.

Bromopyrazoles of Formula XXXI, wherein R1, R2, R3, R5, R8 and X are aspreviously defined, can be allowed to react under Suzuki couplingconditions with a boronic ester such as vinylboronic acid pinacol esteror cyclopropylboronic acid pinacol ester in the presence of a catalystsuch as palladium tetrakis, a base such as 2 M aqueous potassiumcarbonate, and in a mixed solvent system such as ethanol and toluene toprovide compounds of Formula XXXII, as shown in step a of Scheme XV.

The vinyl group of compounds of Formula XXXIII, wherein R1, R2, R3, R5,R6, R8 and X are as previously defined, can be reduced in the presenceof hydrogen with a catalyst such as 10% Pd/C in a polar protic solventsuch methanol to give compounds of Formula XXXIV, as shown in step a ofScheme XVI. Oxidation of the vinyl group of compounds of Formula XXXIIIusing an oxidant such as osmium tetroxide in the presence of sodiumperiodate in mixture of a polar protic solvent such as water and a polaraprotic solvent such as THF gave compounds of Formula XXXV, as shown instep b of Scheme XVI. Reduction of the aldehyde of compounds of FormulaXXXV, as shown in step c of Scheme XVI, with a reducing agent such assodium borohydride in a polar protic solvent such as methanol gave thecorresponding alcohol of Formula XXXVI. Treatment of compounds ofFormula XXXVI with a chlorinating agent such as thionyl chloride in apolar aprotic solvent such as dichloromethane gave compounds of FormulaXXXVII, as shown in step d of Scheme XVI.

In step a of Scheme XVII, an α,β-unsaturated acid XXXVIII can be treatedwith a nucleophile such as sodium thiomethoxide in a polar proticsolvent such as methanol to give acid XXXIX.

In Step a of the Scheme XVIII, treatment of the compounds of Formula Ig,where A is A2, R7 is O and R8 is tert-butoxy with a reagent such aspropargyl bromide in the presence of a base such as sodium hydride andin a polar aprotic solvent such as DMF yields compounds of Formula Ih,wherein R6=R11.

In step a of Scheme XIX, compounds of Formula XL, wherein X, R1, R2, R3,R4, R5 and R6 are as previously defined, can be treated with an acid ofFormula XLI, wherein R8 is as previously defined, in the presence of acoupling reagent, such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (EDC.HCl), and a base, such as N,N-dimethylaminopyridine(DMAP), in a polar aprotic solvent, such as dichloromethane (DCM), toyield compounds of Formula XLII. In step b, compounds of the FormulaXLII can be treated with a base, such as sodium methoxide, in a polarsolvent such as THF, followed by an alkyl halide R9-Hal to give thecompounds of the Formula XLIII.

Alternatively, in step a of Scheme XX, compounds of the Formula XL orthe corresponding HCl salt, wherein X, R1, R2, R3, R4, R5, and R6 are aspreviously defined, can be coupled to acids of the formula XLIV, whereinR8 is as previously defined, in the presence of a coupling reagent, suchas 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(EDC.HCl), and a base, such as N,N-dimethylaminopyridine, in a polaraprotic solvent, such as dichloromethane, to yield compounds of theFormula XLV, wherein X, R1, R2, R3, R4, R5, R6 and R8 are as previouslydefined. In step b of Scheme XX, compounds of the Formula XLV, whereinX, R1, R2, R3, R4, R5, R6 and R8 are as previously defined and Trrepresents trityl (triphenylmethyl), can be treated with an acid, suchas 2,2,2-trifluoroacetic acid, in the presence of a trialkyl silane,such as triethyl silane, in a polar aprotic solvent, such as methylenechloride, to remove the trityl group to give thiols of the Formula XLVI,wherein X, R1, R2, R3, R4, R5, R6 and R8 are as previously defined. Instep c of Scheme XX, thiols of the Formula XLVI, wherein X, R1, R2, R3,R4, R5, R6 and R8 are as previously defined, can be treated with a base,such as sodium hydride, in a polar aprotic solvent such astetrahydrofuran, or cesium carbonate in acetonitrile, or DBU indimethylformamide, and an electrophile (R9-Hal), such as2-(bromomethyl)-1,1-difluorocyclopropane, in tetrahydrofuran, to givecompounds of the Formula XLVII. Alternatively, the modified conditionsdescribed by Pustovit and coworkers (Synthesis 2010, 7, 1159-1165) couldbe employed in the transformation of XLVI to XLVII.

Alternatively, in step a of the Scheme XXI, compounds of the Formula XLor the corresponding HCl salt, wherein X, R1, R2, R3, R4, R5, and R6 areas previously defined, can be coupled to acids of the Formula XLVIII,wherein R9 is as previously defined, in the presence of a couplingreagent such as EDC.HCl and a base such as DMAP in a polar aproticsolvent such as DMF to yield compounds of Formula XLIX, where in X, R1,R2, R3, R4, R5, R6 and R9 are as previously defined. In step b of theScheme XXI, compounds of the Formula XLIX, wherein X, R1, R2, R3, R4,R5, R6 and R9 are as previously defined, can be treated with a thio acidsalt, such as potassium thioacetate, at an elevated temperature (about50° C.) in a solvent, such as DMSO, to give compounds of the Formula L,wherein X, R1, R2, R3, R4, R5, R6 and R9 are as previously defined. Instep c of the Scheme XXI, compounds of the Formula L, wherein X, R1, R2,R3, R4, R5, R6 and R9 are as previously defined, can be treated with anequimolar amount of a base, such as sodium methoxide, prepared frommixing sodium hydride, and methanol, followed by an electrophile(R9-Halo), such as 2-(bromomethyl)-1,1-difluorocyclopropane, in asolvent, such as tetrahydrofuran, to give compounds of the Formula LI.

In step a of Scheme XXII, compounds of the Formula XL, wherein X, R1,R2, R3, R4, R5, R6, and halo are as previously defined, can be treatedwith an acid chloride of Formula LII in the presence of a base, such astriethylamine or diisopropylethylamine in a polar aprotic solvent, suchas DCE, to yield compounds of the Formula LIII, wherein R8 is either asubstituted or unsubstituted alkyl chain. In step b, compounds of theFormula LIII can be treated with potassium thioacetate to providecompounds of Formula LIV after heating (about 60° C.) in a polar aproticsolvent, such as acetone. As indicated in step c, a one-potmethanolysis/alkylation sequence can be achieved via treatment ofcompounds of the Formula LIV with one equivalent of a base, such assodium methoxide (NaOMe) in a polar aprotic solvent, such astetrahydrofuran (THF). An alkyl sulfonate or alkyl halide, such as2-iodo-1,1,1-trifluoroethane, can then be added to the reaction mixtureto deliver compounds of the Formula LV, wherein R9 is as previouslydefined. In step d compounds of the Formula LV may be obtained fromcompounds of the Formula LIII via treatment with an alkyl thiol such as2,2,2-trifluoroethanethiol at elevated temperatures (about 50° C.) in apolar aprotic solvent, such as THF, in the presence of sodium iodide anda base, such as diisopropylethylamine. Alternatively, in step f treatingcompounds of Formula LIII with an alkyl thiol, such as sodiummethanethiolate, in a polar aprotic solvent, such as DMSO, at elevatedtemperatures (about 50° C.) will afford compounds of Formula LV. Asdemonstrated in step e, when compounds of the Formula LIV are treatedwith two or more equivalents of a base, such as NaOMe, followed by a1,2,2-trihaloalkyl compound, such as 2-bromo-1,1-difluoroethane,compounds of Formula LVI are obtained.

In step a of Scheme 23, compounds of Formula 23.1, wherein X, R1, R2,R3, R4, R5, R6 and R8 are as previously defined, can be treated with abase, such as aqueous 2M lithium hydroxide, in a polar protic solvent,such as methanol, to give compounds of Formula 23.2. Then in step b,compounds of Formula 23.2 can be treated with a base, such as sodiumhydride in a polar aprotic solvent, such as tetrahydrofuran, followed byan electrophile, such as an alkyl halide or sulfonyl halide, to affordcompounds of Formula 23.3.

In step a of Scheme 24, compounds of Formula 24.1, where X, R1, R2, R3,R4, R5, R8 and halo are as previously defined, and R6=H, can be treatedwith a base such as sodium hydride, in a polar aprotic solvent, such astetrahydrofuran (THF), to yield compounds of Formula 24.2 where m is aninteger selected from 0,1,2,3,4,5, or 6. In step b of Scheme 24,compounds of Formula 24.2 can be treated with a base, such astriethylamine, and silylation reagents, such as trimethylsilyltrifluoromethanesulfonate and dimethylmethylideneammonium iodide(Eschenmoser's salt) in a polar aprotic solvent, such as dichloromethane(DCM), to yield compounds of Formula 24.3. In step c of Scheme 24,compounds of Formula 24.3 can be treated with a base, such as potassiumhydroxide, and a nucleophile, such as S,S-dimethyl carbonodithioate, inwater and a polar aprotic solvent such as tetrahydrofuran (THF) to yieldcompounds of Formula 24.4, wherein X, R1, R2, R3, R4, R5, R9 and m areas previously defined.

A route to compounds of Formula 25.2 is described in Scheme 25. Asdemonstrated in step a, when compounds of the Formula 25.1, wherein X,R1, R2, R3, R4, R5, R6 and R8 are as previously defined, are treatedwith two or more equivalents of a base, such as sodium methoxide,followed by a 1,2-dihaloalkyl compound, such as 1-fluoro-2-iodoethane,in a solvent, such as tetrahydrofuran (THF), compounds of Formula 25.2,wherein R9 is as previously defined, are obtained.

An alternative route to vinyl sulfides is described in step a of Scheme26. This route utilizes conditions developed by Kao and Lee (Org. Lett.2011, 13, 5204-5207) in which thiols of the Formula 26.1, wherein X, R1,R2, R3, R4, R5, R6 and R8 are as previously defined, are coupled with avinyl halide, such as (E)-1-bromo-3,3,3-trifluoroprop-1-ene, in thepresence of a catalyst, such as copper(I) oxide, a base, such aspotassium hydroxide, and a solvent, such as dioxane, at elevatedtemperatures to afford products of Formula 26.2, wherein R9 is aspreviously defined.

In step a of Scheme 27, an acrylamide of Formula 27.1, wherein X, R1,R2, R3, R4, R5, and R6 are as previously defined, is reacted with asulfonamide of Formula 27.2, wherein R9 is as previously defined, in thepresence of a base, such as potassium carbonate, at elevatedtemperatures in a polar aprotic solvent, such as dimethylformamide(DMF), to deliver compounds of Formula 27.3. This product can then betreated with a base, such as sodium hydride, and an alkyl halide, suchas 2-bromoacetonitrile, in a polar aprotic solvent, such astetrahydrofuran (THF), to provide compounds of the Formula 27.4, asdemonstrated in step b.

When compounds of the Formula 28.1, wherein X, R1, R2, R3, R4, R5, R6,R8 and halo are as previously defined, are treated with amines of theFormula 28.2, wherein R9 is as previously defined, at elevatedtemperatures in a polar protic solvent, such as methanol, compounds ofthe Formula 28.3 can be obtained, as demonstrated in step a of Scheme28. Compounds of the Formula 28.3 may be treated with a sulfonylchloride, such as methanesulfonyl chloride, in the presence of a base,such as diisopropylethylamine, and a polar aprotic solvent, such asdichloromethane (DCM), to afford products of the Formula 28.4, as shownin step b. As demonstrated in step c, when compounds of the Formula 28.3are treated with an alkyl halide, such as3-bromo-1,1,1-trifluoropropane, at elevated temperatures and in thepresence of a base, such as potassium carbonate, and a polar aproticsolvent, such as dimethylformamide (DMF), compounds of the Formula 28.5may be obtained. Alternatively, compounds of Formula 28.3 may beprepared via a two step process as described in steps d and e of Scheme28. Compounds of Formula 28.6 can be converted to compounds of Formula28.8 when treated with compounds of Formula 28.7 in the presence of acoupling reagent such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (EDC.HCl) and a base such as N,N-dimethylaminopyridine(DMAP) in a polar aprotic solvent such as dichloroethane (DCE), as shownin step d. The Boc-group can be removed under conditions that arewell-known in the art, such as under acidic conditions such astrifluoroacetic acid (TFA) in a polar aprotic solvent likedichloromethane to give compounds of Formula 28.3 as in step e.

In step a of Scheme 29, compounds of Formula 29.1, wherein X, R1, R2,R3, R4, R5, R6 and R8 are as previously defined, can be reacted witheither a cyclic or acyclic enone, such as but-3-ene-2-one, under theconditions described by Chakraborti (Org. Lett. 2006, 8, 2433-2436) todeliver compounds of the Formula 29.2, wherein R9 is as previouslydefined. These products may then be subjected to a fluorinating reagent,such as Deoxo-Fluor, and an initiator, such as ethanol, in a polaraprotic solvent, such as dichloromethane (DCM), to deliver compounds ofthe Formula 29.3, as described in step b.

Step a of Scheme 30 depicts the hydrolysis of compounds of the Formula30.1, wherein X, R1, R2, R3, R4, R5, R6, R8, and R9 are as previouslydefined, via treatment with an acid, such as aqueous hydrochloric acid,in a solvent, such as THF, to afford an intermediate aldehyde of theFormula 30.2. Compounds of the Formula 30.2 can be immediately reactedwith a fluorinating reagent, such as Deoxo-Fluor, in the presence of aninitiator, such as ethanol, and a solvent, such as tetrahydrofuran(THF), to provide products of the Formula 30.3.

In Scheme 31, compounds of the Formula 31.1, wherein R9 is as previouslydefined, are converted to compounds of the Formula 31.2 via theprocedure described in Dmowski (J. Fluor. Chem., 2007, 128, 997-1006),as shown in step a. Compounds of Formula 31.2 may then be subjected toconditions described in step b, in which a reaction with a thioate saltin a solvent, such as dimethylformamide (DMF), provides compounds of theFormula 31.3, wherein W is aryl or alkyl. As indicated in step c, aone-pot deprotection/alkylation sequence can be achieved via treatmentof compounds of the Formula 31.3 with one equivalent of a base, such assodium methoxide (NaOMe), in a polar aprotic solvent, such astetrahydrofuran (THF). A compound of the Formula 31.4, wherein X, R1,R2, R3, R4, R5, R6, R8 and halo are as previously defined, may then beadded to the reaction mixture to afford compounds of the Formula 31.5.

In Scheme 32, a neat mixture of an olefin of the Formula 32.1, where nis an integer selected from 0, 1, 2, 3, 4, or 5, and trimethylsilyl2,2-difluoro-2-(fluorosulfonyl)acetate can be heated in the presence ofsodium fluoride to deliver a substituted difluorocyclopropane of theFormula 32.2, as indicated in step a. In step b, this product wastreated with tetrabutylammonium fluoride (TBAF) in tetrahydrofuran (THF)to afford an intermediate homoallylic alcohol of the Formula 32.3. Thisalcohol was not isolated, but rather immediately treated withp-toluenesulfonyl chloride in the presence of pyridine anddichloromethane to afford a tosylate of the Formula 32.4, as shown instep c.

Compounds of the Formula 33.1, wherein X, R1, R2, R3, R4, R5, and R6 areas previously defined, where X is preferably carbon, R1, R2, R3, and R5are hydrogen and R4 is chloro, may be coupled with an acid chloride ofthe Formula 33.2, wherein R8 is as previously defined, in the presenceof a base, such as pyridine, diisopropylethylamine, orN,N-dimethylaminopyridine (DMAP), and a solvent, such as1,2-dichloroethane or methylene choride, to afford products of theFormula 33.3, as depicted in step a of Scheme 33.

In step a of Scheme 33 amines of Formula 33.1 are coupled with acidchlorides of Formula 33.2 in the presence of a base, or combination ofbases such as pyridine, N,N-dimethylaminopyridine, ordiisopropylethylamine. The reaction is carried out in a halogenatedsolvent such as 1,2-dichloroethane or methylene chloride. The reactionis conducted at a temperature from 0° C. to 80° C. and preferably fromabout 0° C. to 23° C. Approximately, a 1:1 molar ratio of the amine offormula 33.1 to acid chloride of Formula 33.2 may be used, however,molar ratios of about 5:1 to about 1:5 may also be used. The reaction isconducted at about atmospheric pressure, however, higher or lowerpressures can be used.

In step a of Scheme 34, the compounds of Formula 34.1, wherein R1, R2,R3, R4, R5 and R6 and X are as previously defined, can be treated withan acid of Formula 34.2, wherein R8 is as previously defined, in thepresence of N,N′-dicyclohexylcarbodiimide (DCC), and a base, such asN,N-dimethylaminopyridine (DMAP), in a solvent, such as diethyl ether(Et₂O), to yield compounds of Formula 34.3.

In step a of Scheme 35, aminopyrazoles of Formula 35.1, wherein X, R1,R2, R3, R4, R5 and R6 are as previously defined, can be treated withphosgene and N,N-dimethylaminopyridine (DMAP) at about 80° C. in a polaraprotic solvent such as dichloroethane (DCE). Subsequently, treatmentwith an amine, as shown in step b, or an alcohol, as shown in step c, ora thiol, as shown in step d, generates a urea of Formula 35.2, acarbamate of Formula 35.3, or a carbamothioate of Formula 35.4, whereinR9 is as previously defined, respectively.

In step a of Scheme 36, compounds of Formula 36.1, wherein X, R1, R2 andR3 are as previously defined, can be treated with a base such astriethylamine, carbon disulfide and a sulfonyl chloride such as4-methylbenzene-1-sulfonyl chloride in a polar aprotic solvent such astetrahydrofuran (THF) to yield compounds of Formula 36.2. In step b ofScheme 36, oxazolidin-2-one can be treated with an equimolar amount of abase, such as sodium hydride followed by compounds of Formula 36.2, in apolar aprotic solvent such as dimethylformamide (DMF) to give compoundsof the Formula 36.3. Additionally, the product of step b, (previous towork-up) can be treated with an electrophile such as iodomethane to givecompounds of Formula 36.4 as demonstrated in step c of Scheme 36.

In step a of Scheme 37, ureas of Formula 37.1, wherein R1, R2, R3, R4,R5, R6, R8, and X are as previously defined, can be reacted with a basesuch as lithium bis(trimethylsilyl)amide in a polar aprotic solvent suchas THF followed by an acyl chloride such as pivaloyl chloride to yieldacylated ureas of Formula 37.2, wherein R1, R2, R3, R4, R5, R6, R8, andX are as previously defined. In step b of Scheme 37, ureas of Formula37.1, wherein R1, R2, R3, R4, R5, R6, R8, and X are as previouslydefined, can be reacted with a base such as lithiumbis(trimethylsilyl)amide in a polar aprotic solvent such as THF followedby an alkyl halide such as (chloromethyl)(methyl)sulfane to yieldalkylated ureas of Formula 37.2, wherein R1, R2, R3, R4, R5, R6, R8, andX are as previously defined. In step c of Scheme 37, ureas of Formula37.1, wherein R1, R2, R3, R4, R5, R6, R8, and X are as previouslydefined, can be reacted with a base such as lithiumbis(trimethylsilyl)amide in a polar aprotic solvent such as THF followedby a sulfonyl chloride such as methanesulfonyl chloride to yieldsulfonylated ureas of Formula 37.3, wherein R1, R2, R3, R4, R5, R6, R8,and X are as previously defined.

In step a of Scheme 38, amines of Formula 38.1, wherein R6 is H or Me,can be reacted with an electrophile of Formula 38.2, wherein R8 and R9are as previously defined, such as naphthalen-2-ylmethyl3-(methylthio)propanimidothioate hydrobromide in a polar protic solventsuch as ethanol followed by exposure to a base such as MP-Carbonate in apolar protic solvent such as methanol to give amidines of Formula 38.3,wherein R6 is H or Me, and R8 and R9 are as previously defined.

In step a of the Scheme 39, compounds of the Formula 39.1, wherein X,R1, R2, R3, R4, R5, R6 and R8 are as previously defined, can be treatedwith alcohols of the Formula 39.2, wherein R9 is as previously defined,in the presence of a base such as sodium hydride or potassiumtert-butoxide in a polar aprotic solvent such as THF at appropriatetemperatures, to give the corresponding ethers of the Formula 39.3.Alternatively, in step b of Scheme 39, thioethers of the Formula 39.5can be obtained by treating compounds of the Formula 39.1, wherein X,R1, R2, R3, R4, R5, R6 and R8 are as previously defined, with thiols ofthe Formula 39.4, wherein R9 is as previously defined, in the presenceof a base such as sodium hydride in an aprotic solvent such as THF.

In Scheme 40, compounds of the Formula 40.1, wherein X, R1, R2, R3, R4,R5, R6 and R8 are as previously defined, can be treated according to theconditions of Estrada et. al. (Synlett, 2011, 2387-2891), to give thecorresponding sulfonamides of the Formula 40.2, wherein R9 is aspreviously defined with the proviso that at least one of the R9 is notH.

In step a of Scheme 41, compounds of the Formula 41.1, wherein X, R1,R2, R3, R4, R5 and R6 are as previously defined, can be coupled to acidsof the Formula 41.2, wherein R8 and R9 are as previously defined, in thepresence of a coupling reagent such as EDC.HCl and a base such as DMAPin an aprotic solvent such as dichloromethane to give phosphonates ofthe Formula 41.3. In step b of Scheme 41, phosphonates of the Formula41.3, wherein X, R1, R2, R3, R4, R5, R6, R8 and R9 are as previouslydefined, can be treated with carbonyl compounds of the Formula 41.4,where R9 is as previously defined in the presence of a base such assodium hydride in an aprotic solvent such as THF to give thecorresponding alkenes of the Formula 41.5.

In step a of the Scheme 42, compounds of the Formula 42.1, wherein X,R1, R2, R3, R4, and R5, are as previously defined, can be treated withtrifluoroacetic anhydride in the presence of a base such astriethylamine in an aprotic solvent such as dichloromethane to giveamides of the Formula 42.2, where X, R1, R2, R3, R4, and R5, are aspreviously defined. In step b of Scheme 42, amides of the Formula 42.2,wherein X, R1, R2, R3, R4, and R5, are as previously defined, can betreated with an alkylating agent such as iodomethane in the presence ofa base such as potassium tert-butoxide in a solvent such as THF toafford compounds of the Formula 42.3. In step c of the Scheme 42 amidesof the Formula 42.3, wherein X, R1, R2, R3, R4, and R5, are aspreviously defined can be treated under basic conditions such aspotassium carbonate and methanol to give the corresponding amines of theFormula 42.4.

EXAMPLES

The examples are for illustration purposes and are not to be construedas limiting the invention disclosed in this document to only theembodiments disclosed in these examples.

Starting materials, reagents, and solvents that were obtained fromcommercial sources were used without further purification. Anhydroussolvents were purchased as Sure/Seal™ from Aldrich and were used asreceived. Melting points were obtained on a Thomas Hoover Unimeltcapillary melting point apparatus or an OptiMelt Automated Melting PointSystem from Stanford Research Systems and are uncorrected. Molecules aregiven their known names, named according to naming programs within ISISDraw, ChemDraw or ACD Name Pro. If such programs are unable to name amolecule, the molecule is named using conventional naming rules. All NMRshifts are in ppm (6) and were recorded at 300, 400 or 600 MHz unlessotherwise stated. Examples using “room temperature” were conducted inclimate controlled laboratories with temperatures ranging from about 20°C. to about 24° C.

Example 1 Step 1: Preparation of3,3-bis-methylsulfanyl-1-pyridin-3-yl-propenone

To a room-temperature suspension of sodium hydride (NaH, 60% suspensionin mineral oil; 4.13 g, 86 mmol) in dry dimethyl sulfoxide (DMSO, 60 mL)under an atmosphere of nitrogen (N₂) was added 3-acetylpyridine (5.00 g,41.3 mmol) dropwise over 30 minutes (min). The mixture was stirred foran additional 30 minutes at the same temperature. Carbon disulfide (CS₂;3.27 g, 43 mmol) was added dropwise with vigorous stirring followed byiodomethane (12.21 g, 86 mmol) dropwise over a period of 45 min.Stirring was continued for an additional 18 hours (h) under N₂. Thereaction was quenched with cold water (H₂O, 50 mL). The dark solid wasfiltered and washed with ice-cold ethyl alcohol (EtOH) until thewashings were colorless. The off-white solid product was dried undervacuum at 60° C. to provide3,3-bis-methylsulfanyl-1-pyridin-3-yl-propenone as a brown solid (4.8 g,51%): ¹H NMR (300 MHz, CDCl₃) δ 9.13 (d, J=1.8 Hz, 1H), 8.72 (dd, J=4.8,1.6 Hz, 1H), 8.23 (ddd, J=7.9, 2, 2 Hz, 1H), 7.40 (dd, J=7.9, 4.8 Hz,1H), 6.73 (s, 1H), 2.58 (d, J=9.4 Hz, 6H); MS m/z 226.2 (M+1).

1-(5-fluoropyridin-3-yl)-3,3-bis(methylthio)prop-2-en-1-one was preparedas described in Example 1, Step 1: mp 150-152° C.; ¹H NMR (400 MHz,CDCl₃) δ 8.93 (t, J=1.6 Hz, 1H), 8.58 (d, J=2.8 Hz, 1H), 7.94 (ddd,J=8.9, 2.8, 1.7 Hz, 1H), 6.69 (s, 1H), 2.60 (s, 3H), 2.57 (s, 3H).

Example 1 Step 2: Preparation of(Z)-3-methylamino-3-methylsulfanyl-1-pyridin-3-yl-propenone

A solution of 3,3-bis-methylsulfanyl-1-pyridin-3-yl-propenone (18.6 g,82.5 mmol) in absolute alcohol (400 mL) under N₂ was treated withmethylamine hydrochloride (27.86 g, 412 mmol) followed by triethylamine(Et₃N; 58.5 mL, 412 mmol). The mixture was heated to reflux for 3 h,cooled to room temperature and concentrated under reduced pressure. Thesolid residue was dissolved in ethyl acetate (EtOAc; 150 mL). Thesolution was washed with H₂O (2×50 mL) and brine (50 mL), dried overNa₂SO₄, concentrated under reduced pressure and purified by silica gelchromatography eluting with 10% EtOAc in petroleum ether to yield(Z)-3-methylamino-3-methylsulfanyl-1-pyridin-3-yl-propenone as a paleyellow solid (8.6 g, 50%): ¹H NMR (300 MHz, CDCl₃) δ 11.8 (br s, 1H),9.06 (s, 1H); 8.67 (d, J=3.9 Hz, 1H), 8.26 (d, J=8.0 Hz 1H), 7.46 (dd,J=7.6, 4.9 Hz 1H), 5.62 (s, 1H), 3.10 (d, J=5.2 Hz, 3H), 2.52 (s, 3H);MS (m/z) 209.2 [M+1].

(Z)-3-(ethylamino)-3(methylthio)-1-(pyridin-3-yl)prop-2-en-1-one wasprepared as described in Example 1, Step 2: ¹H NMR (400 MHz, CDCl₃) δ11.81 (bs, 1H), 9.04 (dd, J=2.2, 0.7 Hz, 1H), 8.64 (dd, J=4.8, 1.7 Hz,1H), 8.29-7.98 (m, 1H), 7.35 (ddd, J=7.9, 4.8, 0.9 Hz, 1H), 3.45 (q,J=7.2, 5.6 Hz, 2H), 2.50 (s, 3H), 1.35 (t, J=7.2 Hz, 3H).

(Z)-3-(cyclopropylmethyl)amino-3(methylthio)-1-(pyridin-3-yl)prop-2-en-1-onewas prepared as described in Example 1, Step 2: ¹H NMR (400 MHz, CDCl₃)δ 9.00 (s, 1H), 9.05 (dd, J=2.2, 0.7 Hz, 1H), 8.64 (dd, J=4.8, 1.7 Hz,1H), 8.16 (dt, J=7.9, 2.0 Hz, 1H), 7.35 (ddd, J=7.9, 4.8, 0.8 Hz, 1H),5.62 (s, 1H), 3.27 (dd, J=7.0, 5.5 Hz, 2H), 2.50 (s, 3H), 1.20-1.07 (m,1H), 0.73-0.49 (m, 2H), 0.41-0.17 (m, 2H).

Example 1 Step 3: Preparation ofmethyl-(2-methyl-5-pyridin-3-pyrazol-3-yl)-amine

A solution of(Z)-3-methylamino-3-methylsulfanyl-1-pyridin-3-yl-propenone (3.00 g, 14mmol) and methylhydrazine (729 mg, 15.4 mmol) in absolute EtOH (64 mL)was stirred at reflux for 18 h under N₂, cooled to room temperature andevaporated under reduced pressure. The residue was dissolved in EtOAc(50 mL), and the organic layer was washed with H₂O (2×30 mL) and brine(30 mL), dried over Na₂SO₄, concentrated under reduced pressure andpurified using silica gel chromatography eluting with a gradient of 0-1%EtOH in EtOAc to yield two regioisomers in a 1:2 ratio, with the majorregioisomer as a brown solid (1.0 g, 27%): ¹H NMR (300 MHz, CDCl₃) δ8.97 (d, J=1.3 Hz, 1H), 8.51 (dd, J=3.6, 1.0 Hz, 1H), 8.07 (ddd, J=5.9,1.4, 1.4 Hz, 1H), 7.30 (dd, J=5.9, 3.6 Hz, 1H), 5.82 (s, 1H), 3.69 (s,3H), 2.93 (s, 3H); MS (m/z) 188.6 [M+1].

1-Ethyl-N-methyl-3-(pyridin-3-yl)-1H-pyrazol-5-amine was prepared asdescribed in Example 1, Step 3: ESIMS m/z 204 ([M+2H]).

N-ethyl-1-methyl-3-(pyridin-3-yl)-1H-pyrazol-5-amine was prepared asdescribed in Example 1, Step 3: ESIMS m/z 203 ([M+H]).

N-methyl-1-phenyl-3-(pyridin-3-yl)-1H-pyrazol-5-amine was prepared asdescribed in Example 1, Step 3: ESIMS m/z 252 ([M+2H]).

N-(cyclopropylmethyl)-1-methyl-3-(pyridin-3-yl)-1H-pyrazol-5-amine wasprepared as described in Example 1, Step 3: ESIMS m/z 230 ([M+2H]).

1-Isopropyl-N-methyl-3-pyridin-3-yl)-1H-pyrazol-5-amine was prepared asdescribed in Example 1, Step 3: ¹H NMR (300 MHz, CDCl₃) δ 8.53 (s, 1H),8.06-7.90 (m, J=7.2 Hz, 2H), 7.13 (dd, J=7.9, 5.6 Hz, 1H), 5.33 (s, 1H),3.70 (bs, 1H), 3.65 (dt, J=13.2, 6.6 Hz, 1H), 2.31 (s, 3H), 0.88 (d,J=6.6 Hz, 6H); ESIMS m/z 217 ([M+H]). 3-(5-Fluoropyridin-3-yl)-N,1-dimethyl-1H-pyrazol-5-amine was prepared as described in Example 1,Step 3: ¹H NMR (300 MHz, CDCl₃) δ 8.28 (s, 1H), 7.87 (t, J=1.3 Hz, 1H),7.60 (m, 1H), 6.66 (s, 1H), 5.28 (bs, 2H), 3.12 (s, 3H), 2.34 (s, 3H);ESIMS m/z 206 ([M+H])

Example 2 Preparation of(4-chloro-2-methyl-5-pyridin-3-yl-2H-pyrazol-3-yl)-methyl-amine

A mixture of methyl-(2-methyl-5-pyridin-3-yl-2H-pyrazol-3-yl)-amine(0.35 g, 1.8 mmol) and N-chlorosuccinimide (0.273 g, 2 mmol) wascombined in acetonitrile (3 mL), stirred at room temperature for 30minutes, concentrated under reduced pressure and purified using silicagel chromatography eluting with a gradient of EtOAc in hexanes to yieldthe title compound as a yellow oil (0.096 g, 23%): IR (thin film) 1581.6cm⁻¹; H NMR (400 MHz, CDCl₃) δ 9.12 (d, J=1.5 Hz, 1H), 8.57 (dd, J=4.8,1.3 Hz, 1H), 8.15 (ddd, J=7.8, 2.0, 2.0 Hz, 1H), 7.33 (dd, J=8.1, 5.1Hz, 1H), 3.80 (s, 3H), 2.91 (d, J=5.8 Hz, 3H); ESIMS (m/z) 225.6 [M+2].

The reaction also gave4-chloro-2-methyl-5-pyridin-3-yl-2H-pyrazol-3-ylamine as a green gum(0.046 g, 13%): IR (thin film) 1720.5 cm⁻¹; ¹H NMR (CDCl₃, 400 MHz) δ9.13 (br s, 1H), 8.57 (br s, 1H), 8.16 (dt, J=8.0, 2.0 Hz, 1H), 7.33(dd, J=7.8, 4.8 Hz, 1H), 3.76 (s, 3H); ESIMS (m/z) 207.0 [M−1].

Example 3 Preparation of2,N-dimethyl-N-(2-methyl-5-pyridin-3-yl-2H-pyrazol-3-yl)-3-methylsulfanyl-propionamide(Compound 1)

To a solution of methyl-(2-methyl-5-pyridin-3-yl-2H-pyrazol-3-yl)-amine(150 mg, 0.8 mmol) under N₂ in ice-cold dichloroethane (DCE; 2 mL) wasadded dropwise via pipette a solution of2-methyl-3-methylsulfanyl-propionylchloride (146 mg, 0.9 mmol) in DCE(1.5 mL). After stirring for 10 minutes (min), a solution of4-N,N-dimethylaminopyridine (DMAP; 107 mg, 0.9 mmol) in DCE (2 mL) wasadded dropwise. The ice bath was removed after 30 min, and the mixturewas stirred at room temperature for 90 min and then at reflux for 14 h.The mixture was concentrated under reduced pressure and was purified bysilica gel chromatography eluting with a gradient of EtOAc in hexane.The product,2,N-dimethyl-N-(2-methyl-5-pyridin-3-yl-2H-pyrazol-3-yl)-3-methylsulfanyl-propionamide,was isolated as a yellow semi-solid (44 mg, 24%): ¹H NMR (400 MHz,CDCl₃) δ 9.00 (s, 1H), 8.58 (s, 1H), 8.08 (br d, J=7.0 Hz, 1H), 7.35 (brdd, J=7.3, 4.8 Hz, 1H), 6.58 (br s, 0.5H), 6.49 (br s, 0.5H), 3.89-3.79(m, 3H), 3.25 (s, 3H), 2.96-2.80 (m, 1H), 2.42-2.40 (m, 1H), 2.02-1.99(m, 3H), 2.62 (m, 1H), 1.15 (d, J=6.0 Hz, 3H); MS (m/z) 305.0 [M+1].

Compounds 2-6, 9-10, 12, 18-21, 24-33, 477, 487, 509, 520, 556-557,562-568 were made from the appropriate amines in accordance with theprocedures disclosed in Example 3.

Example 4 Preparation of1-methyl-1-(2-methyl-5-pyridin-3-yl-2H-pyrazol-3-yl)-3-(2-methylsulfanyl-ethyl)-urea(Compound 7)

To a solution of methyl-(2-methyl-5-pyridin-3-yl-2H-pyrazol-3-yl)-amine(150 mg, 0.8 mmol) in ice-cold DCE (2 mL) under N₂ was added a solutionof phosgene in toluene (20%, 0.43 mL, 0.88 mmol). The ice bath wasremoved after 30 min, and the mixture was stirred at room temperaturefor 1 h and at reflux for 2 h. The mixture was cooled to roomtemperature and then more phosgene (0.86 mL, 1.76 mmol) was added. Themixture was stirred at reflux for 90 min and then cooled in an ice bath.To this was added a solution of 2-methylthioethylamine (80 mg, 0.88mmol) in DCE (2 mL). The ice bath was removed after 10 min, and thereaction mixture was stirred at reflux for 14 h, cooled, and dilutedwith DCE (30 mL). The diluted reaction mixture was washed with saturatedNaHCO₃ (20 mL), dried over MgSO₄, adsorbed onto silica gel and purifiedusing silica gel chromatography eluting with a gradient of methanol indichloromethane to afford1-methyl-1-(2-methyl-5-pyridin-3-yl-2H-pyrazol-3-yl)-3-(2-methylsulfanyl-ethyl)-ureaas a yellow gum (14 mg, 6%): ¹H NMR (400 MHz, CDCl₃) δ 8.99 (d, J=1.5Hz, 1H), 8.57 (dd, J=4.8, 1.5 Hz, 1H), 8.08 (ddd, J=8.1, 2.1, 2.1 Hz,1H), 7.34 (dd, J=7.9, 4.8 Hz, 1H), 6.52 (s, 1H), 4.88 (br t, J=5.5 Hz,1H), 3.80 (s, 3H), 3.41 (q, J=6.3 Hz, 2H), 3.24 (s, 3H), 2.61 (t, J=6.3,2H), 2.06 (s, 3H); ESIMS (m/z) 292.2 [M+2].

Compound 8 was made in accordance with the procedures disclosed inExample 4 using 2-(methylthio)ethanol in place of2-methylthioethylamine.

Example 5 Preparation of 1-methyl-5-(pyridin-3-yl)-1H-pyrazol-3-amineand 1-methyl-3-(pyridin-3-yl)-1H-pyrazol-5-amine

To ethanol (8.53 mL) was added 3-oxo-3-(pyridin-3-yl)propanenitrile(0.82 g, 5.61 mmol) and methylhydrazine (0.25 g, 5.61 mmol) and stirredat reflux for 2 hours. The reaction was cooled to room temperature andconcentrated to dryness. The crude material was purified by silica gelchromatography by eluting with 0-20% MeOH/dichloromethane to yield twoproducts—1-methyl-5-(pyridin-3-yl)-1H-pyrazol-3-amine (0.060 g; 6.14%):¹H NMR (300 MHz, CDCl₃) δ 8.72 (s, 1H), 8.53 (d, 1H), 7.76-7.63 (m, 1H),7.43-7.33 (m, 1H), 5.75 (s, 1H), 3.76-3.57 (m, 5H) and1-methyl-3-(pyridin-3-yl)-1H-pyrazol-5-amine (0.150 g, 15.35%): ¹H NMR(300 MHz, CDCl₃) δ 8.88 (s, 1H), 8.48 (d, 1H), 7.99 (d, 1H), 7.38-7.07(m, 1H), 585 (s, 1H), 3.80-3.59 (m, 5H).

Example 6 Step 1: Preparation of 3-pyrazol-1-yl-pyridine

To a solution of 3-bromopyridine (5 g, 0.031 mol) in 50 ml ofacetonitrile were added pyrazole (2.6 g, 0.038 mol), Cs₂CO₃ (16.5 g,0.050 mol), Cu₂O (0.226 g, 0.0016 mol), and salicylaldoxime (0.867 g,0.006 mol) under N₂ atmosphere. The reaction mass was refluxed for 24hrs at 80° C. The reaction mass was concentrated and the crude waspurified by column chromatography using ethyl acetate and hexane (1:1)to afford the pyrazolyl pyridine as a dark brown liquid (2 g, 43%): ¹HNMR (400 MHz, CDCl₃) δ 8.99 (d, J=2.8 Hz, 1H), 8.48 (dd, J=4.8, 1.2 Hz,1H), 8.11-8.08 (m, 1H), 7.99 (d, J=1.2 Hz, 1H), 7.78 (d, J=1.2 Hz, 1H),7.38-7.35 (m, 1H), 6.53 (t, J=1.2 Hz, 1H); MS (m/z) 146 [M+1].

3-(3-chloro-1H-pyrazol-1-yl)pyridine was prepared as in Example 6, Step1: mp 98-106° C.; ¹H NMR (400 MHz, CDCl₃) δ 8.93 (d, J=2.6 Hz, 1H), 8.57(dd, J=4.8, 1.4 Hz, 1H), 8.03 (ddd, J=8.3, 2.7, 1.5 Hz, 1H), 7.90 (d,J=2.5 Hz, 1H), 7.42 (ddd, J=8.3, 4.8, 0.7 Hz, 1H), 6.46 (d, J=2.5 Hz,1H); ¹³C (DMSO-d₆) 148, 142, 140, 136, 131, 126, 125, 108.

2-methyl-3-(3-methyl-1H-pyrazol-1-yl)pyridine was prepared as in Example6, Step 1: ¹H NMR (400 MHz, CDCl₃) δ 8.53 (d, J=4.7 Hz, 1H), 7.67 (d,J=7.9 Hz, 1H), 7.54 (t, J=8.0 Hz, 1H), 7.27-7.19 (m, 1H), 6.27 (d, J=1.4Hz, 1H), 2.53 (s, 3H), 2.38 (s, 3H).

3-(3-(Trifluoromethyl)-1H-pyrazol-1-yl)pyridine was prepared from theappropriate starting materials as described in Example 6, Step 1: mp59.0-61.0° C.; ¹H NMR (400 MHz, CDCl₃) δ 9.00 (s, 1H), 8.70-8.59 (m,1H), 8.11 (ddd, J=8.3, 2.7, 1.5 Hz, 1H), 8.05-7.98 (m, 1H), 7.46 (dd,J=8.3, 4.8 Hz, 1H), 6.79 (d, J=2.4 Hz, 1H); EIMS m/z 213.

3-Fluoro-5-(3-methyl-1H-pyrazol-1-yl)pyridine was prepared from theappropriate starting materials as described in Example 6, Step 1: mp70.0-72.0° C.; ¹H NMR (400 MHz, CDCl₃) δ 8.76-8.73 (m, 1H), 8.37-8.33(m, 1H), 7.88-7.85 (m, 1H), 7.84-7.79 (m, 1H), 6.34-6.29 (m, 1H), 2.37(s, 3H); EIMS m/z 177.

3-(3-Chloro-1H-pyrazol-1-yl)-5-fluoropyridine was prepared from theappropriate starting materials as described in Example 6, Step 1: mp77.0-82.0° C.; ¹H NMR (400 MHz, CDCl₃) δ 8.75 (d, J=1.8 Hz, 1H), 8.43(d, J=2.3 Hz, 1H), 7.92 (d, J=2.6 Hz, 1H), 7.84 (dt, J=9.3, 2.4 Hz, 1H),6.48 (d, J=2.6 Hz, 1H); EIMS m/z 198.

3-(3-methyl-1H-pyrazol-1-yl)pyridine was prepared as described inExample 6, Step 1: ¹H NMR (400 MHz, CDCl₃) δ 8.94 (bs, 1H), 8.51 (d,J=3.9 Hz, 1H), 8.02 (ddd, J=8.3, 2.6, 1.5 Hz, 1H), 7.90-7.79 (m, 1H),7.39 (dd, J=8.2, 5.1 Hz, 1H), 6.30 (d, J=2.4 Hz, 1H), 2.39 (s, 3H).

3-(5-methyl-1H-pyrazol-1-yl)pyridine was prepared as in Example 6, Step1: ¹H NMR (400 MHz, CDCl₃) δ 8.77 (d, J=2.5 Hz, 1H), 8.65 (dd, J=4.8,1.5 Hz, 1H), 7.84 (ddd, J=8.2, 2.5, 1.5 Hz, 1H), 7.63 (d, J=1.6 Hz, 1H),7.44 (ddd, J=8.2, 4.8, 0.7 Hz, 1H), 6.225 (dd, J=1.6, 0.7 Hz, 1H), 2.40(s, 3H).

Example 6 Step 2: Preparation of 3-(4-nitro-pyrazol-1-yl)-pyridine

3-Pyrazol-1-yl-pyridine (2 g, 0.032 mol) was dissolved in concentratedH₂SO₄ (32 mL 0.598 mmol) and cooled at −5° C. using an ice bath. To thereaction mass, a 1:1 mixture of concentrated HNO₃ (30 mL, 0.673 mmol)and concentrated H₂SO₄ (30 ml, 15 Vol.) was added dropwise over a periodof 30 min. Cooling was discontinued and the reaction mixture was stirredat room temperature overnight. After the reaction was complete, themixture was poured over crushed ice and neutralized with saturatedNaHCO₃, filtered, washed with water and dried to furnish the nitropyrazole as pale yellow solid (1.8 g, 68%): ¹H NMR (400 MHz, DMSO-d₆) δ9.03 (d, J=2.8 Hz, 1H); 8.70 (dd, J=4.8, 1.6 Hz, 1H), 8.69 (s, 1H), 8.33(s, 1H), 8.11-8.08 (m, 1H), 7.51 (dd, J=8.4, 4.8 Hz, 1H); MS (m/z) 191[M+1].

3-(3-chloro-4-nitro-1H-pyrazol-1-yl)pyridine was prepared as in Example6, Step 2: mp 139-142° C., ¹H NMR (400 MHz, CDCl₃) δ 9.01 (d, J=2.0 Hz,1H), 8.73 (d, J=4.9 Hz, 2H), 8.08 (ddd, J=8.3, 2.5, 1.3 Hz, 1H), 7.52(dd, J=8.3, 4.8 Hz, 1H), EIMS m/z 224.

3-(5-methyl-4-nitro-1H-pyrazol-1-yl)pyridine was prepared as in Example6, Step 2: ¹H NMR (400 MHz, CDCl₃) δ 8.81-8.71 (m, 2H), 8.32 (s, 1H),7.83 (ddd, J=8.2, 2.5, 1.6 Hz, 1H), 7.54 (dd, J=8.2, 4.8 Hz, 1H), 2.72(s, 3H).

2-methyl-3-(3-methyl-4-nitro-1H-pyrazol-1-yl)pyridine was prepared as inExample 6, Step 2: ¹H NMR (400 MHz, d₆-DMSO) δ 14.01 (s, 1H), 9.37 (d,J=4.0 Hz, 1H), 8.69 (t, J=17.3 Hz, 1H), 8.21 (dd, J=7.7, 4.8 Hz, 1H),2.29 (s, 3H), 2.20 (s, 3H); ¹³C 154, 150, 146, 135, 134.9, 134.8, 134.3,122, 21, 14; EIMS m/z 218.

3-(3-methyl-4-nitro-1H-pyrazol-1-yl)pyridine was prepared as in Example6, Step 2: mp 122-124° C.; ¹H NMR (400 MHz, CDCl₃) δ 9.01 (d, J=2.5 Hz,1H), 8.77-8.56 (m, 2H), 8.07 (ddd, J=8.3, 2.7, 1.5 Hz, 1H), 7.56-7.37(m, 1H), 2.66 (s, 3H); EIMS m/z 208.

3-Fluoro-5-(3-methyl-4-nitro-1H-pyrazol-1-yl)pyridine was prepared fromthe appropriate starting material as described in Example 6, Step 2: mp90.0-92.0° C.; ¹H NMR (400 MHz, CDCl₃) δ 8.82 (d, J=2.0 Hz, 1H), 8.69(s, 1H), 8.54 (d, J=2.5 Hz, 1H), 7.89 (dt, J=8.9, 2.4 Hz, 1H), 2.66 (s,3H); EIMS m/z 222.

3-(4-Nitro-3-(trifluoromethyl)-1H-pyrazol-1-yl)pyridine was preparedfrom the appropriate starting material as described in Example 6, Step2: mp 121.0-123.0° C.; ¹H NMR (400 MHz, CDCl₃) δ 9.04 (d, J=2.5 Hz, 1H),8.79 (s, 1H), 8.77 (d, J=0.9 Hz, 1H), 8.13 (ddd, J=8.3, 2.7, 1.4 Hz,1H), 7.55 (dt, J=10.8, 5.4 Hz, 1H); EIMS m/z 258.

3-(3-Chloro-4-nitro-1H-pyrazol-1-yl)-5-fluoropyridine was prepared fromthe appropriate starting material as described in Example 6, Step 2: mp109.5-111.0° C.; ¹H NMR (400 MHz, CDCl₃) δ 8.83 (d, J=2.1 Hz, 1H), 8.75(s, 1H), 8.60 (d, J=2.4 Hz, 1H), 7.89 (dt, J=8.6, 2.4 Hz, 1H); EIMS m/z242.

3-(3-Bromo-4-nitro-1H-pyrazol-1-yl)pyridine was prepared from theappropriate starting material as described in Example 6, Step 2: mp139.0-141.0° C.; ¹H NMR (400 MHz, CDCl₃) δ 9.01 (d, J=2.5 Hz, 1H), 8.73(dd, J=4.7, 1.1 Hz, 1H), 8.71 (s, 1H), 8.15-8.00 (m, 1H), 7.52 (dd,J=8.3, 4.8 Hz, 1H); ESIMS m/z 271 ([M+2]⁺).

Example 6 Step 3: Preparation of 1-pyridin-3-yl-1H-pyrazol-4-ylamine

To a solution of 3-(4-nitro-pyrazol-1-yl)-pyridine (1.8 g, 0.009 mol) indry THF (18 mL) was added 5% Pd/C (180 mg) under nitrogen atmosphere.The mixture was then stirred under hydrogen atmosphere until thereaction was complete. The reaction mixture was filtered through a padof celite, and concentrated to dryness to give an impure dark brownsolid (1.76 g): ¹H NMR (400 MHz, DMSO-d₆) δ 8.89 (dd, J=2.8. 0.4 Hz,1H); 8.48 (dd, J=4.8, 1.2 Hz, 1H), 7.99-7.96 (m, 1H), 7.54 (d, J=1.2 Hz,1H), 7.45 (d, J=0.4 Hz, 1H), 7.38-7.35 (m, 1H), 4.81 (bs 1H); ESIMS(m/z) 161 [M+1].

5-methyl-1-(pyridin-3-yl)-1H-pyrazol-4-amine was prepared as in Example6, Step 3: ¹H NMR (400 MHz, CDCl₃) δ 8.74 (d, J=2.3 Hz, 1H), 8.63-8.50(m, 1H), 7.81 (ddd, J=8.2, 2.5, 1.5 Hz, 1H), 7.46-7.33 (m, 2H), 2.64(bs, 1H), 2.29 (s, 3H); ¹³C (DMSO-d₆) 147, 144, 137, 133, 130, 129, 124,123, 10; EIMS m/z 174

3-methyl-1-(pyrimidin-5-yl)-1H-pyrazol-4-amine was prepared as inExample 6, Step 3: mp 211-215° C.; ¹H NMR (400 MHz, CDCl₃) δ 9.10-8.87(m, 3H), 7.51 (s, 1H), 3.24 (bs, 2H), 2.29 (s, 3H); ESIMS m/z 176([M+H]).

3-chloro-1-(pyrimidin-5-yl)-1H-pyrazol-4-amine was prepared as inExample 6, Step 3: mp 146-148° C.; ¹H NMR (400 MHz, CDCl₃) δ 9.07 (s,1H), 9.02 (s, 2H), 7.52 (s, 1H), 3.45 (s, 2H); ESIMS m/z 196 ([M+H]).

Example 7 Preparation of methyl-(1-pyridin-3-yl-1H-pyrazol-4-yl)-amine

To a 25 ml round bottom flask containing1-pyridin-3-yl-1H-pyrazol-4-ylamine (1.76 g, 0.011 mol) in ethanol (26.4mL) was added benzotriazole (1.31 g, 0.011 mol). The reaction was cooledat 0° C.-10° C. and formaldehyde (0.36 mL, 0.0121 mol) was added slowlyand kept for 30 min at this temperature. The reaction was filtered andconcentrated to dryness. The crude material (2.56 g, 0.009 mol) wasdissolved in dry tetrahydrofuran (25.6 mL), cooled to 0° C. and sodiumborohydride (0.326 g, 0.00882 mol.) was added over 15 min. The reactionwas warmed to room temperature and stirred for 2 hours. The reaction waspoured into water and extracted using dichloromethane, the organic layerwas dried over anhydrous Na₂SO₄ and concentrated to dryness. Purifiedthe crude material by silica gel chromatography eluting with 20%methanol/chloroform to afford the desired product as a brown solid(0.610 g, 32%): ¹H NMR (400 MHz, d₆-DMSO) δ 8.92 (d, J=2.4 Hz, 1H), 8.47(dd, J=4.8, 1.6 Hz, 1H), 8.01-7.98 (m, 1H), 7.45 (s, 1H), 7.30 (s, 1H),7.37 (dd, J=8.0, 4.4 Hz, 1H), 2.84 (s, 3H); ESIMS m/z 175 ([M+1]).

Method B:

1-pyridin-3-yl-1H-pyrazol-4-ylamine (1.0 g, 6.2 mmol) was dissolved intriethyl orthoformate (5 mL, 30 mmol) and to that was addedtrifluoroacetic acid (3-4 drops). The reaction mixture was refluxed at120° C. for 3 hours and was then concentrated. The crude was dissolvedin ethanol (5 ml), cooled to 0° C. and treated with sodium borohydride(0.6 g, 15.7 mmol). After warming to room temperature, the mixture wasrefluxed for 3 hours. The mixture was concentrated and the residue wassuspended between water and diethyl ether. The diethyl ether layer wasseparated and concentrated to dryness. The crude material was purifiedby silica gel chromatography, eluting with 5% methanol/chloroform toafford the desired product as a pale yellow solid (0.3 g, 27%): mp65-67° C.; ¹H NMR (300 MHz, CDCl₃) δ 8.91 (bs, 1H), 8.46 (d, J=4.5 Hz,1H), 7.99 (d, J=8.3 Hz, 1H), 7.43 (s, 1H), 7.41 (s, 1H), 7.36 (dd,J=8.3, 4.7 Hz, 1H), 2.86 (d, J=12.4 Hz, 3H); ESIMS m/z 175 ([M+1]).

Example 8 Preparation of ethyl-(1-pyridin-3-yl-1H-pyrazol-4-yl)-amine

Method A:

To 1-pyridin-3-yl-1H-pyrazol-4-ylamine (0.5 g, 3.12 mmol) indichloromethane (5 mL) was added acetyl chloride (0.28 g, 3.75 mmol)followed by DMAP (0.57 g, 4.68 mmol) and stirred at room temperature for3 hours. The reaction mixture was concentrated and purified by silicagel column chromatography. The recovered material was dissolved intetrahydrofuran (5 mL) and lithium aluminum hydride (0.23 g, 6.25 mmol)was added and stirred at room temperature for 12 hours. The reaction wasquenched with saturated Na₂SO₄ and filtered through celite. The filtratewas collected and concentrated to dryness. The crude material waspurified by silica gel column chromatography eluting with 0-5%methanol/chloroform and resubjected to silica gel chromatography,eluting with 0-100% ethyl acetate/hexanes) to give the desired product(0.080 g, 14%): ¹H NMR (400 MHz, CDCl₃) δ 8.90 (d, J=2.7 Hz, 1H), 8.46(dd, J=4.7, 1.3 Hz, 1H), 7.98 (ddd, J=8.3, 2.6, 1.5 Hz, 1H), 7.41 (dt,J=13.3, 6.6 Hz, 2H), 7.36 (ddd, J=8.3, 4.7, 0.7 Hz, 1H), 3.10 (q, J=7.1Hz, 2H), 1.27 (t, 3H).

Method B:

To a solution of tert-butylethyl(1-(pyridin-3-yl)-1H-pyrazol-4-yl)carbamate (3.4 g, 11.79 mmol) indichloromethane (4.54 mL) was added trifluoroacetic acid (9 mL), and thereaction mixture was stirred for 1 hour at room temperature. Toluene wasadded and the reaction was concentrated to near dryness. The reactionwas poured into a separatory funnel and carefully quenched withsaturated aqueous NaHCO₃ and extracted with dichloroethane.

The organic layer was dried (MgSO₄), filtered and concentrated todryness. The crude product was purified by silica gel chromatography(0-10% MeOH/dichloromethane) to give the desired product as a paleyellow oil (2.10 g, 95%): ¹H NMR (400 MHz, CDCl₃) δ 8.90 (dd, J=1.8, 0.8Hz, 1H), 8.51-8.39 (m, 1H), 7.97 (ddt, J=8.3, 2.7, 1.3 Hz, 1H), 7.41 (d,J=0.8 Hz, 2H), 7.38-7.30 (m, 1H), 3.21-2.93 (m, 2H), 1.34-1.19 (m, 3H).

3-chloro-N-ethyl-1-(pyridin-3-yl)-1H-pyrazol-4-amine was prepared asdescribed in Example 8, Method B: ¹H NMR (400 MHz, CDCl₃) δ 8.87 (d,J=2.5 Hz, 1H), 8.47 (dd, J=4.7, 1.2 Hz, 1H), 7.96 (ddd, J=8.4, 2.6, 1.4Hz, 1H), 7.38-7.32 (m, 2H), 3.11 (q, J=7.1 Hz, 2H), 2.97 (bs, 1H), 1.31(t, J=7.1 Hz, 3H).

3-chloro-N-methyl-1-(pyridin-3-yl)-1H-pyrazol-4-amine was prepared as inExample 8, Method B: mp 108-118 C; ¹H NMR (400 MHz, CDCl₃) δ 8.88 (d,J=2.4 Hz, 1H), 8.48 (dd, J=4.7, 1.4 Hz, 1H), 7.96 (ddd, J=8.3, 2.7, 1.4Hz, 1H), 7.41-7.29 (m, 2H), 2.87 (s, 3H); EIMS m/z 208.

N,3-dimethyl-1-(pyridin-3-yl)-1H-pyrazol-4-amine was prepared as inExample 8, Method B: ¹H NMR (400 MHz, CDCl₃) δ 9.03-8.73 (m, 1H), 8.41(dd, J=4.7, 1.4 Hz, 1H), 7.95 (ddd, J=8.4, 2.7, 1.4 Hz, 1H), 7.42-7.27(m, 2H), 2.85 (s, 4H), 2.25 (s, 3H); EIMS m/z 189

3-chloro-N-(cylopropylmethyl)-1-(pyridin-3-yl)-1H-pyrazol-4-amine wasprepared as in Example 8, Method B: ¹H NMR (400 MHz, CDCl₃) δ 8.86 (d,J=2.5 Hz, 1H), 8.47 (dd, J=4.7, 1.4 Hz, 1H), 8.03-7.89 (m, 1H),7.40-7.29 (m, 2H), 3.21 (s, 1H), 2.91 (d, J=4.4 Hz, 2H), 1.18-1.02 (m,1H), 0.65-0.45 (m, 2H), 0.41-0.12 (m, 2H).

3-chloro-N-propyl-1-(pyridin-3-yl)-1H-pyrazol-4-amine was prepared as inExample 8, Method B: ¹H NMR (400 MHz, CDCl₃) δ 8.86 (d, J=2.6 Hz, 1H),8.47 (dd, J=4.7, 1.4 Hz, 1H), 8.01-7.89 (m, 1H), 7.42-7.27 (m, 2H),3.23-2.84 (m, 3H), 1.77-1.59 (m, 2H), 1.03 (t, J=7.4 Hz, 3H).

1-(5-Fluoropyridin-3-yl)-N, 3-dimethyl-1H-pyrazol-4-amine was preparedfrom the appropriate Boc-amine as described in Example 8, Method B: mp142.0-143.5° C.; ¹H NMR (400 MHz, CDCl₃) δ 8.67 (s, 1H), 8.26 (d, J=2.3Hz, 1H), 7.73 (dt, J=10.0, 2.4 Hz, 1H), 7.27 (s, 1H), 2.92-2.81 (m, 4H),2.24 (s, 3H); ESIMS m/z 207 ([M+H]⁺).

N-ethyl-1-(5-fluoropyridin-3-yl)-3-methyl-1H-pyrazol-4-amine wasprepared from the appropriate Boc-amine as described in Example 8,Method B: mp 85.0-86.0° C.; ¹H NMR (400 MHz, CDCl₃) δ 8.66 (s, 1H), 8.25(d, J=2.5 Hz, 1H), 7.72 (dt, J=10.0, 2.3 Hz, 1H), 7.27 (s, 1H), 3.07 (q,J=7.1 Hz, 2H), 2.71 (s, 1H), 2.25 (s, 3H), 1.30 (t, J=7.1 Hz, 3H); ESIMSm/z 221 ([M+H]⁺).

3-Methyl-N-propyl-1-(pyridin-3-yl)-1H-pyrazol-4-amine was prepared fromthe appropriate Boc-amine as described in Example 8, Method B: mp65.0-67.0° C.; ¹H NMR (400 MHz, CDCl₃) δ 8.86 (d, J=2.4 Hz, 1H), 8.40(dd, J=4.7, 1.4 Hz, 1H), 7.94 (ddd, J=8.3, 2.7, 1.5 Hz, 1H), 7.35-7.28(m, 2H), 3.00 (t, J=7.1 Hz, 2H), 2.26 (s, 3H), 1.76-1.58 (m, 2H), 1.03(t, J=7.4 Hz, 3H); ESIMS m/z 217 ([M+H]⁺).

N-(cyclopropylmethyl)-3-methyl-1-(pyridin-3-yl)-1H-pyrazol-4-amine wasprepared from the appropriate Boc-amine as described in Example 8,Method B: mp 73.0-75.0° C.; ¹H NMR (400 MHz, CDCl₃) δ 8.86 (d, J=2.4 Hz,1H), 8.40 (dd, J=4.7, 1.3 Hz, 1H), 7.94 (ddd, J=8.3, 2.6, 1.5 Hz, 1H),7.35-7.28 (m, 2H), 2.87 (d, J=6.9 Hz, 2H), 2.75 (s, 1H), 2.28 (s, 3H),1.22-1.05 (m, 1H), 0.63-0.56 (m, 2H), 0.26 (q, J=4.7 Hz, 2H); ESIMS m/z229 ([M+H]⁺).

N-isopropyl-3-methyl-1-(pyridin-3-yl)-1H-pyrazol-4-amine was preparedfrom the appropriate Boc-amine as described in Example 8, Method B: IR(thin film) 3303 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 8.86 (d, J=2.3 Hz, 1H),8.41 (dd, J=4.7, 1.4 Hz, 1H), 7.94 (ddd, J=8.3, 2.7, 1.5 Hz, 1H),7.36-7.28 (m, 2H), 3.30 (hept, J=6.3 Hz, 1H), 2.25 (s, 3H), 1.24 (d,J=6.3 Hz, 6H); EIMS m/z 216.

5-Ethoxy-1-(5-fluoropyridin-3-yl)-N,3-dimethyl-1H-pyrazol-4-amine wasprepared from the appropriate Boc-amine as described in Example 8,Method B: IR (thin film) 3340 cm⁻¹; H NMR (400 MHz, CDCl₃) δ 8.91 (s,1H), 8.31 (d, J=2.5 Hz, 1H), 7.88-7.80 (m, 1H), 4.24 (q, J=7.1 Hz, 2H),2.79 (s, 3H), 2.24 (s, 3H), 1.36 (t, J=7.1 Hz, 3H); EIMS m/z 250.

5-Bromo-N-methyl-1-(pyridin-3-yl)-1H-pyrazol-4-amine was prepared fromthe appropriate Boc-amine as described in Example 8, Method B: mp77.0-79.0° C.; ¹H NMR (400 MHz, CDCl₃) δ 8.90 (d, J=2.0 Hz, 1H), 8.63(d, J=3.9 Hz, 1H), 7.93 (ddd, J=8.2, 2.4, 1.5 Hz, 1H), 7.51 (s, 1H),7.43 (dd, J=8.2, 4.8 Hz, 1H), 4.49 (s, 1H), 2.91 (s, 3H); ESIMS m/z 255([M+2]⁺).

5-Fluoro-N, 3-dimethyl-1-(pyridin-3-yl)-1H-pyrazol-4-amine was preparedfrom the appropriate Boc-amine as described in Example 8, Method B: ¹HNMR (400 MHz, CDCl₃) δ 8.91 (t, J=2.1 Hz, 1H), 8.50 (dd, J=4.8, 1.5 Hz,1H), 7.93 (ddt, J=8.3, 2.8, 1.5 Hz, 1H), 7.37 (ddd, J=8.3, 4.8, 0.7 Hz,1H), 2.86 (d, J=1.6 Hz, 3H), 2.43 (s, 2H), 2.24 (s, 3H); EIMS m/z 206.

5-Bromo-N, 3-dimethyl-1-(pyridin-3-yl)-1H-pyrazol-4-amine was preparedfrom the appropriate Boc-amine as described in Example 8, Method B: ¹HNMR (400 MHz, CDCl₃) δ 8.86 (dd, J=2.5, 0.5 Hz, 1H), 8.59 (dd, J=4.8,1.5 Hz, 1H), 7.88 (ddd, J=8.2, 2.6, 1.5 Hz, 1H), 7.40 (ddd, J=8.2, 4.8,0.7 Hz, 1H), 2.85 (s, 3H), 2.69 (s, 1H), 2.35 (s, 3H); ESIMS m/z 268([M+H]⁺).

5-Chloro-N, 3-dimethyl-1-(pyridin-3-yl)-1H-pyrazol-4-amine was preparedfrom the appropriate Boc-amine as described in Example 8, Method B: ¹HNMR (400 MHz, CDCl₃) δ 8.87 (d, J=2.3 Hz, 1H), 8.59 (dd, J=4.8, 1.3 Hz,1H), 7.90 (ddd, J=8.2, 2.6, 1.5 Hz, 1H), 7.40 (ddd, J=8.2, 4.8, 0.6 Hz,1H), 2.87 (s, 3H), 2.45-2.19 (m, 4H); EIMS m/z 223.

3-Chloro-1-(5-fluoropyridin-3-yl)-N-methyl-1H-pyrazol-4-amine wasprepared from the appropriate Boc-amine as described in Example 8,Method B: mp 117.5-119.0° C.; ¹H NMR (400 MHz, CDCl₃) δ 8.68 (d, J=1.1Hz, 1H), 8.33 (d, J=2.5 Hz, 1H), 7.75 (dt, J=9.6, 2.4 Hz, 1H), 7.31 (s,1H), 3.14 (s, 1H), 2.87 (s, 3H); ESIMS m/z 227 ([M]⁺).

3-Chloro-N-ethyl-1-(5-fluoropyridin-3-yl)-1H-pyrazol-4-amine amine wasprepared from the appropriate Boc-amine as described in Example 8,Method B: ¹H NMR (400 MHz, CDCl₃) δ 8.70-8.63 (m, 1H), 8.32 (d, J=2.4Hz, 1H), 7.74 (dt, J=9.7, 2.4 Hz, 1H), 7.31 (s, 1H), 3.11 (q, J=7.2 Hz,2H), 1.31 (t, J=7.1 Hz, 3H).

1-(5-Fluoropyridin-3-yl)-N-methyl-3-vinyl-1H-pyrazol-4-amine wasprepared from the appropriate Boc-amine as described in Example 8,Method B: 105.0-107.0° C.; ¹H NMR (400 MHz, CDCl₃) δ 8.72 (s, 1H), 8.31(d, J=2.5 Hz, 1H), 7.81 (dt, J=9.8, 2.4 Hz, 1H), 7.33 (s, 1H), 6.75 (dd,J=18.0, 11.6 Hz, 1H), 5.83 (dd, J=18.0, 1.1 Hz, 1H), 5.46 (dd, J=11.6,1.1 Hz, 1H), 2.86 (s, 3H); ESIMS m/z 219 ([M+H]⁺).

3-Cyclopropyl-1-(5-fluoropyridin-3-yl)-N-methyl-1H-pyrazol-4-amine wasprepared from the appropriate Boc-amine as described in Example 8,Method B: mp 118.0-119.5° C.; ¹H NMR (400 MHz, CDCl₃) δ 8.66-8.58 (m,1H), 8.23 (d, J=2.5 Hz, 1H), 7.75-7.68 (m, 1H), 7.25 (s, 1H), 3.09 (s,1H), 2.86 (s, 3H), 1.78-1.63 (m, 1H), 0.99-0.90 (m, 4H); ESIMS m/z 233([M+H]⁺).

3-Chloro-1-(pyridin-3-yl)-1H-pyrazol-4-amine was prepared from theappropriate Boc-amine as described in Example 8, Method B: mp137.9-139.9; ¹H NMR (400 MHz, CDCl₃) δ 8.84 (d, J=2.4 Hz, 1H), 8.50 (dd,J=4.7, 1.4 Hz, 1H), 7.95 (ddd, J=8.3, 2.7, 1.5 Hz, 1H), 7.52 (s, 1H),7.37 (ddd, J=8.4, 4.7, 0.7 Hz, 1H), 3.18 (s, 2H); ESIMS m/z 196([M+H]⁺).

2-((3-Chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)amino)acetonitrile wasprepared fromtert-butyl(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)(cyanomethyl)carbamateas in Example 8, Method B: mp 141-143° C.; ¹H NMR (300 MHz, CDCl₃) δ8.91 (d, J=2.7 Hz, 1H), 8.54 (dd, J=5.1, 1.8 Hz, 1H), 7.97 (m, 1H), 7.62(s, 1H), 7.38 (dd, J=12.0, 7.5 Hz, 1H), 4.97 (d, J=6.9 Hz, 2H), 3.52 (m,1H); EIMS m/z 235 ([M+1]⁺).

N-3-dimethyl-1-(pyrimidin-5-yl)-1H-pyrazol-4-amine was prepared as inExample 8, Method B: mp 139-143° C.; ¹H NMR (400 MHz, CDCl₃) δ 9.02 (s,2H), 9.00 (s, 1H), 7.30 (s, 1H), 2.87 (d, J=11.5 Hz, 3H), 2.27 (s, 3H);ESIMS m/z 190 ([M+H]).

3-chloro-N-methyl-1-(pyrimidin-5-yl)1-1H-pyrazol-4-amine was prepared asin Example 8, Method B: mp 111-114° C.; ¹H NMR (400 MHz, CDCl₃) δ9.09-9.04 (m, 1H), 9.02 (s, 2H), 7.30 (s, 1H), 3.14 (bs, 1H), 2.88 (s,3H); ESIMS m/z 196 ([M+H]).

1-(5-Fluoro-3-pyridyl)-3-methyl-N-(trideuteriomethyl)pyrazol-4-amine wasprepared from compound 380 using the procedure as described in Example8, method B: mp 146-148° C.; ¹H NMR (400 MHz, CDCl₃) δ 8.67 (s, 1H),8.25 (d, J=2.5 Hz, 1H), 7.73 (dt, J=10.0, 2.3 Hz, 1H), 7.27 (s, 1H),2.87 (s, 1H), 2.24 (s, 3H); ESIMS m/z 210 ([M+H]⁺); IR (Thin film) 1599cm⁻¹.

3-Chloro-1-(3-pyridyl)-N-(trideuteriomethyl)pyrazol-4-amine was preparedfrom compound 381 using the procedure as described in Example 8, methodB: mp 104-106° C.; ¹H NMR (400 MHz, CDCl₃) δ 8.87 (d, J=1.9 Hz, 1H),8.47 (d, J=4.7 Hz, 1H), 8.00-7.90 (m, 1H), 7.40-7.30 (m, 2H), 3.10 (s,1H); ESIMS m/z 212 ([M+H]⁺); IR (Thin film) 1579 cm⁻¹.

3-Chloro-N-(cyclopropylmethyl)-1-(pyridin-3-yl)-1H-pyrazol-4-amine wasprepared from compound 361 using the procedure as described in Example8, method B: mp 82-83° C.; ¹H NMR (400 MHz, CDCl₃) δ 8.86 (d, J=2.5 Hz,1H), 8.47 (dd, J=4.7, 1.3 Hz, 1H), 7.95 (ddd, J=8.4, 2.7, 1.5 Hz, 1H),7.38-7.32 (m, 2H), 3.22 (s, 1H), 2.90 (d, J=6.9 Hz, 2H), 1.23-1.06 (m,1H), 0.65-0.53 (m, 2H), 0.31-0.19 (m, 2H).; ESIMS m/z 249 ([M+H]⁺);

3-Chloro-N-propyl-1-(pyridin-3-yl)-1H-pyrazol-4-amine was prepared fromcompound 360 using the procedure as described in Example 8, method B: mp92-94° C.; ¹H NMR (400 MHz, CDCl₃) δ 8.86 (d, J=2.6 Hz, 1H), 8.47 (dd,J=4.7, 1.4 Hz, 1H), 7.95 (ddd, J=8.3, 2.7, 1.5 Hz, 1H), 7.35 (ddd,J=8.4, 4.7, 0.6 Hz, 1H), 7.33 (s, 1H), 3.22-2.94 (m, 3H), 1.75-1.52 (m,2H), 1.02 (t, J=7.4 Hz, 3H); ESIMS m/z 237 ([M+H]⁺).

3-Chloro-1-(pyridin-3-yl)-N-(4,4,4-trifluorobutyl)-1H-pyrazol-4-aminewas prepared from the appropriate Boc-amine as described in Example 8,Method B: IR (thin film) 3416, 3089 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 8.86(d, J=2.5 Hz, 1H), 8.48 (dd, J=4.7, 1.3 Hz, 1H), 7.95 (ddd, J=8.3, 2.7,1.4 Hz, 1H), 7.42-7.31 (multiple peaks, 2H), 3.16 (dd, J=13.0, 6.5 Hz,2H), 3.08 (d, J=5.6 Hz, 1H), 2.35-2.18 (m, 2H), 2.00-1.86 (m, 2H); ESIMSm/z 307 ([M+2H]⁺).

3-Chloro-1-(pyridin-3-yl)-N-(5,5,5-trifluoropentyl)-1H-pyrazol-4-aminewas prepared from the appropriate Boc-amine as described in Example 8,Method B: IR (thin film) 3087 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 8.86 (d,J=2.5 Hz, 1H), 8.48 (dd, J=4.7, 1.4 Hz, 1H), 7.96 (ddd, J=8.3, 2.7, 1.5Hz, 1H), 7.36 (ddd, J=8.3, 4.8, 0.6 Hz, 1H), 7.34 (s, 1H), 3.10 (s, 2H),3.04 (s, 1H), 2.30-1.98 (m, 2H), 1.84-1.69 (multiple peaks, 4H); ¹⁹F NMR(376 MHz, CDCl₃) δ-66.28; ESIMS m/z 320 ([M+2H]⁺).

3-Chloro-N-(4-fluorobutyl)-1-(pyridin-3-yl)-1H-pyrazol-4-amine wasprepared from the appropriate Boc-amine as described in Example 8,Method B: mp 82-83° C.; IR (thin film) 3348, 3086 cm⁻¹; ¹H NMR (400 MHz,CDCl₃) δ 8.86 (d, J=2.5 Hz, 1H), 8.47 (dd, J=4.7, 1.4 Hz, 1H), 7.95(ddd, J=8.3, 2.7, 1.5 Hz, 1H), 7.38-7.33 (multiple peaks, 2H), 4.58 (t,J=5.7 Hz, 1H), 4.50-4.42 (m, 1H), 3.11 (multiple peaks, 3H), 1.90-1.76(multiple peaks, 4H); ESIMS m/z 269 ([M+H]⁺).

3-Chloro-N-isopropyl-1-(pyridin-3-yl)-1H-pyrazol-4-amine was preparedfrom the appropriate Boc-amine as described in Example 8, Method B: IR(thin film) 3318, 1583 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 8.86 (d, J=2.7Hz, 1H), 8.47 (dd, J=4.7, 1.4 Hz, 1H), 7.96 (ddd, J=8.4, 2.7, 1.5 Hz,1H), 7.36 (ddd, J=8.3, 4.8, 0.7 Hz, 1H), 7.31 (s, 1H), 2.87 (d, J=6.8Hz, 2H), 1.92 (dq, J=13.4, 6.7 Hz, 1H), 1.02 (d, J=6.7 Hz, 6H); ESIMSm/z 251 ([M+H]⁺).

3-Chloro-N-(2-methoxyethyl)-1-(pyridin-3-yl)-1H-pyrazol-4-amine wasprepared from the appropriate Boc-amine as described in Example 8,Method B: IR (thin film) 3364, 1485 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 8.86(dd, J=2.7, 0.7 Hz, 1H), 8.48 (dd, J=4.7, 1.5 Hz, 1H), 7.96 (ddd, J=8.4,2.7, 1.5 Hz, 1H), 7.38 (s, 1H), 7.38-7.34 (m, 1H), 3.68-3.59 (m, 2H),3.49 (s, 1H), 3.42 (s, 3H), 3.24 (d, J=7.3 Hz, 2H); ESIMS m/z 253([M+H]⁺).

3-Chloro-N-((2,2-difluorocyclopropyl)methyl)-1-(pyridin-3-yl)-1H-pyrazol-4-aminewas prepared from the appropriate Boc-amine as described in Example 8,Method B: H NMR (400 MHz, CDCl₃) δ 8.87 (d, J=2.6 Hz, 1H), 8.49 (dd,J=4.7, 1.5 Hz, 1H), 7.96 (ddd, J=8.4, 2.7, 1.4 Hz, 1H), 7.41 (s, 1H),7.37 (ddd, J=8.3, 4.7, 0.7 Hz, 1H), 3.19 (td, J=15.5, 13.0, 6.8 Hz, 2H),2.00-1.84 (m, 1H), 1.55 (m, 1H), 1.26 (s, 1H), 1.23-1.11 (m, 1H); ¹⁹FNMR (376 MHz, CDCl₃) δ-128.61 (d, J=159.5 Hz), −143.58 (d, J=160.0 Hz);ESIMS m/z 285 ([M+H]⁺).

3-Chloro-N-(3-fluoropropyl)-1-(pyridin-3-yl)-1H-pyrazol-4-amine wasprepared from the appropriate Boc-amine as described in Example 8,Method B: IR (thin film) 3359 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 8.87 (d,J=2.7 Hz, 1H), 8.48 (dd, J=4.7, 1.4 Hz, 1H), 7.95 (ddd, J=8.3, 2.6, 1.4Hz, 1H), 7.39-7.34 (multiple peaks, 2H), 4.63 (dt, J=47.2, 5.6 Hz, 2H),3.25 (t, J=6.7 Hz, 2H), 3.18 (br s, 1H), 2.17-1.92 (m, 2H); ESIMS m/z255 ([M+H]⁺).

N-allyl-3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-amine was prepared fromthe appropriate Boc-amine as described in Example 8, Method B: IR (thinfilm) 3291 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 8.85 (d, J=2.6 Hz, 1H), 8.48(dd, J=4.8, 1.5 Hz, 1H), 7.95 (ddd, J=8.3, 2.7, 1.4 Hz, 1H), 7.38-7.35(m, 1H), 7.34 (s, 1H), 5.97 (ddt, J=17.3, 10.6, 5.5 Hz, 1H), 5.34 (dq,J=17.2, 1.6 Hz, 1H), 5.23 (dq, J=10.3, 1.5 Hz, 1H), 3.73 (dt, J=5.5, 1.6Hz, 2H), 3.25 (s, 1H); ESIMS m/z 235 ([M+H]⁺).

2-((3-Chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)amino)ethyl acetate wasprepared from the appropriate Boc-amine as described in Example 8,Method B: IR (thin film) 3361, 1733 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 8.87(s, 1H), 8.49 (d, J=4.7 Hz, 1H), 7.96 (ddd, J=8.3, 2.7, 1.4 Hz, 1H),7.43 (s, 1H), 7.37 (dd, J=8.4, 4.7 Hz, 1H), 4.30 (dd, J=5.9, 4.8 Hz,2H), 3.34 (t, J=5.5 Hz, 2H), 2.12 (s, 3H), 1.59 (s, 1H); ESIMS m/z 281([M+H]⁺).

3-Chloro-N-(2-fluoroethyl)-1-(pyridin-3-yl)-1H-pyrazol-4-amine wasprepared from the appropriate Boc-amine as described in Example 8,Method B: IR (thin film) 3369 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 8.86 (d,J=2.7 Hz, 1H), 8.49 (dd, J=4.7, 1.4 Hz, 1H), 7.96 (ddd, J=8.3, 2.7, 1.5Hz, 1H), 7.40 (s, 1H), 7.37 (dd, J=8.3, 4.7 Hz, 1H), 4.82-4.53 (m, 2H),3.54-3.27 (multiple peaks, 3H); ESIMS m/z 241 ([M+H]⁺).

3-Chloro-1-(pyridin-3-yl)-N-(2-(pyrrolidin-1-yl)ethyl)-1H-pyrazol-4-aminewas prepared from the appropriate Boc-amine as described in Example 8,Method B: ESIMS m/z 292 ([M+H]⁺).

3-Chloro-N-(2,2-difluoroethyl)-1-(pyridin-3-yl)-1H-pyrazol-4-amine wasprepared from the appropriate Boc-amine as described in Example 8,Method B: IR (thin film) 3295 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 8.87 (dd,J=2.8, 0.7 Hz, 1H), 8.51 (dd, J=4.7, 1.4 Hz, 1H), 7.95 (ddd, J=8.4, 2.7,1.5 Hz, 1H), 7.45 (s, 1H), 7.37 (ddd, J=8.5, 4.7, 0.8 Hz, 1H), 5.96 (tt,J=55.9, 4.1 Hz, 1H), 3.69-3.26 (multiple peaks, 3H); ¹⁹F NMR (376 MHz,CDCl₃) δ-122.15; ESIMS m/z 259 ([M+H]⁺).

3-Chloro-1-(pyridin-3-yl)-N-(2,2,2-trifluoroethyl)-1H-pyrazol-4-aminewas prepared from the appropriate Boc-amine as described in Example 8,Method B: IR (thin film) 3309 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 8.92-8.85(m, 1H), 8.52 (dd, J=4.8, 1.4 Hz, 1H), 7.98 (ddd, J=8.4, 2.7, 1.5 Hz,1H), 7.47 (s, 1H), 7.40 (ddd, J=8.4, 4.8, 0.7 Hz, 1H), 3.68 (q, J=8.9Hz, 2H), 3.49 (s, 1H); ¹⁹F NMR (376 MHz, CDCl₃) δ-72.29; ESIMS m/z 277([M+H]⁺).

3-Chloro-N-(2-chloroethyl)-1-(pyridin-3-yl)-1H-pyrazol-4-amine wasprepared from the appropriate Boc-amine as described in Example 8,Method B: IR (thin film) 3354 cm⁻¹; H NMR (400 MHz, CDCl₃) δ 8.86 (dd,J=2.7, 0.7 Hz, 1H), 8.50 (dd, J=4.8, 1.5 Hz, 1H), 7.96 (ddd, J=8.3, 2.7,1.4 Hz, 1H), 7.40 (s, 1H), 7.37 (ddd, J=8.5, 4.8, 0.8 Hz, 1H), 3.76 (dd,J=6.0, 5.4 Hz, 2H), 3.54 (s, 1H), 3.43 (t, J=5.7 Hz, 2H); ESIMS m/z 257([M+H]⁺).

3-Chloro-1-(pyridin-3-yl)-N-(3,3,3-trifluoropropyl)-1H-pyrazol-4-aminewas prepared from the appropriate Boc-amine as described in Example 8,Method B: IR (thin film) 3366, 3081 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 8.87(dd, J=2.6, 0.7 Hz, 1H), 8.50 (dd, J=4.7, 1.4 Hz, 1H), 7.96 (ddd, J=8.3,2.7, 1.4 Hz, 1H), 7.40-7.35 (multiple peaks, 2H), 3.38 (q, J=6.8 Hz,2H), 3.22 (t, J=6.7 Hz, 1H), 2.48 (qt, J=10.7, 7.0 Hz, 2H); ¹⁹F NMR (376MHz, CDCl₃) δ-64.99; ESIMS m/z 291 ([M+H]⁺).

N-(but-2-yn-1-yl)-3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-amine wasprepared from the appropriate Boc-amine as described in Example 8,Method B: IR (thin film) 3249, 3122 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 8.89(dd, J=2.7, 0.7 Hz, 1H), 8.49 (dd, J=4.8, 1.5 Hz, 1H), 7.98 (ddd, J=8.3,2.7, 1.5 Hz, 1H), 7.50 (s, 1H), 7.37 (ddd, J=8.4, 4.8, 0.8 Hz, 1H),3.93-3.68 (m, 2H), 3.33 (s, 1H), 1.83 (t, J=2.4 Hz, 3H); ESIMS m/z 247([M+H]⁺).

3-Chloro-N-isobutyl-1-(pyridin-3-yl)-1H-pyrazol-4-amine was prepared asin Example 8, Method B: ¹H NMR (400 MHz, CDCl₃) δ 8.86 (d, J=2.5 Hz,1H), 8.47 (dd, J=4.7, 1.3 Hz, 1H), 7.95 (ddd, J=8.4, 2.7, 1.5 Hz, 1H),7.35 (ddd, J=8.3, 4.7, 0.6 Hz, 1H), 7.31 (s, 1H), 3.11 (bs, 1H), 2.87(t, J=6.5 Hz, 2H), 1.93 (dp, J=13.4, 6.7 Hz, 1H), 1.01 (d, J=6.7 Hz,6H).

Example 9 Preparation ofisopropyl-(1-pyridin-3-yl-1H-pyrazol-4-yl)-amine

1-pyridin-3-yl-1H-pyrazol-4-ylamine (0.6 g, 3.7 mmol) was dissolved inisopropyl acetate (8.5 mL). To the mixture, acetone (0.261 g, 4.5 mmol),trifluoroacetic acid (0.855 g, 7.5 mmol) and sodiumtriacetoxyborohydride (0.945 g, 4.5 mmol) were added. The reaction wasstirred under nitrogen at room temperature for 4.5 hours and thenquenched with 10% sodium hydroxide solution until the pH reached ˜9. Thelayers were separated, and the aqueous phase was extracted with ethylacetate. The organic extracts were combined, dried over sodium sulfateand concentrated to dryness. The crude material was purified by silicagel chromatography (gradient elution of 5% methanol/dichloromethane) togive the title compound as an off white solid (0.35 g, 46%): mp 105-107°C.; ¹H NMR (300 MHz, CDCl₃) δ 8.82 (d, J=2.2 Hz, 1H), 8.63 (dd, J=4.8,1.5 Hz, 1H), 8.13 (d, J=1.8 Hz, 1H), 8.03 (d, J=2.7 Hz, 1H), 7.94-7.77(m, 1H), 7.38 (dt, J=15.2, 7.6 Hz, 1H), 6.99 (t, 1H), 3.72 (m, 1H), 1.30(t, J=10.0 Hz, 6H). ESIMS 214 m/z (M+1).

Example 10 Preparation of propyl-(1-pyridin-3-yl-1H-pyrazol-4-yl-amine

To 1-pyridin-3-yl-1H-pyrazol-4-ylamine (0.5 g, 3.12 mmol) indichloromethane (5 mL) was added propionaldehyde (0.18 g, 3.12 mmol) andsodium triacetoxy borohydride (0.99 g, 4.68 mmol) and stirred at roomtemperature for 16 hours. The reaction was taken up in dichloromethaneand was washed with water and brine. The organic layer was dried(MgSO₄), filtered and concentrated to dryness. The crude material waspurified by silica gel chromatography eluting with 0-5%MeOH/Dichloromethane and resubjected in 0-100% ethylacetate/hexanes) togive the title compound as a dark oil (0.05 g, 7%): ¹H NMR (300 MHz,CDCl₃) δ 8.92 (d, J=2.6 Hz, 1H), 8.48 (dd, J=4.7, 1.4 Hz, 1H), 8.00(ddd, J=8.3, 2.7, 1.5 Hz, 1H), 7.47-7.40 (m, 2H), 7.37 (dd, J=8.3, 4.7Hz, 1H), 3.04 (t, J=7.1 Hz, 3H), 1.92-1.46 (m, 2H), 1.03 (t, J=7.4 Hz,3H).

Example 11 Preparation ofN-methyl-N-(1-pyridin-3-yl-1H-pyrazol-4-yl)-isobutyramide (Compound 42)

A solution of isobutyryl chloride (0.138 g, 1.3 mmol) in dichloroethane(1 mL) was pipetted at a dropwise rate into an ice-cold suspension ofmethyl-(1-pyridin-3-yl-1H-pyrazol-4-yl)-amine (0.15 g, 0.86 mmol) indichloroethane (5 mL), stirred for 10 minutes and then treated at adropwise rate with a solution of 4-N,N-dimethylaminopyridine (0.11 g,0.9 mmol) in dichloroethane (1.5 mL). The cooling bath was removed after30 minutes, stirred under nitrogen at room temperature for 14 hours,diluted with dichloroethane (40 mL), washed with water (30 mL), brine(10 mL), dried over MgSO₄ and purified by reversed phase columnchromatography to give a yellowish gum (0.114 g, 54%) ¹H NMR (300 MHz,CDCl₃) δ 9.01-8.93 (m, 1H), 8.67 (s, 0.4H), 8.61 (d, J=4.2 Hz, 0.6H),8.54 (d, 0.4H), 8.08-8.02 (m, 1H), 7.96 (s, 0.6H), 7.80 (s, 0.4H), 7.70(s, 0.6H), 7.47-7.37 (m, 1H), 3.49 (s, 1.2H), 3.26 (s, 2.8H), 3.06-2.98(m, 0.4H), 2.86-2.70 (m, 0.6H), 1.25 (d, J=6.1 Hz, 2.4H), 1.09 (d, J=6.6Hz, 3.6H). ESIMS m/z 245 ([M+1]).

Compounds 32-41, 43-52, 54-56, 59-61, 66, 73-75, 77-79, 82-85, 93-100,113, 117-129, 131-134, 139-140, 142-144, 148, 160, 163, 173-175,184-186, 197-198, 202, 208, 215-217, 252-253, 277, 282-285, 287-290,314-316, 347, 350-351, 353-355, 365-367, 370, 388, 395, 399-403, 407,409, 415-418, 444-449, 452-454, 462-463, 465, 467-469, 496-498, 506-507,512, 525-527, 569, 577, 581, 591 and 592 were made from the appropriateamines in accordance with the procedures disclosed in Example 11.

Example 12 Preparation of4,4,4-trifluoro-2-methyl-N-(1-(pyridin-3-yl)-1H-pyrazol-4-yl)butanamide(Compound 65)

To a solution of 1-(pyridin-3-yl)-1H-pyrazol-4-amine (0.150 g, 0.93mmol) in dichloroethane (1.8 mL) was added4,4,4-trifluoro-2-methylbutanoic acid (0.14 g, 0.93 mmol) and4-N,N-dimethylaminopyridine (0.23 g, 1.87 mmol) followed by1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.36 g,1.87 mmol). The reaction stirred at room temperature overnight. Thereaction mixture was concentrated and the crude product was purified bysilica gel chromatography eluting with 0-5% MeOH/dichloromethane to givea white solid (0.15 g, 55%); mp 140-145° C.; ¹H NMR (400 MHz, CDCl₃) δ9.00 (d, J=2.4 Hz, 1H), 8.62-8.47 (m, 2H), 8.01 (ddd, J=8.3, 2.7, 1.5Hz, 1H), 7.68 (s, 1H), 7.53 (bs, 1H), 7.40 (ddd, J=8.3, 4.8, 0.6 Hz,1H), 2.92-2.61 (m, 2H), 2.32-2.05 (m, 1H), 1.38 (d, J=6.6 Hz, 3H); ESIMSm/z 300 ([M+2]).

Compounds 53, 58, 62-63, 72, 76, 80-81, 107-108, 136-138, 147, 151-159,164-168, 176-179, 187-196, 201, 203-207, 209-214, 220, 224-249, 251,259-275, 286, 292-296, 303-313, 323-326, 341-344, 356-359, 371, 378-379,382, 384, 419-426, 439-443, 455, 458-461, 464, 466, 476, 486, 490-493,505, 508, 517, 528-529, 536-537, 539-541, 544-545, 549-554, 572-577,578, 579 and 580 were prepared from the appropriate amines in accordancewith the procedures disclosed in Example 12.

Example 13 Preparation of tert-butyl1-(pyridin-3-yl)-1H-pyrazol-4-ylcarbamate (Compound 57)

Method A:

To a solution of 1-(pyridin-3-yl)-1H-pyrazol-4-amine (3 g, 18.73 mmol)in dichloromethane (33.4 mL) was added triethylamine (3.13 mL, 7.68mmol) and BOC-anhydride (4.5 g, 20.60 mmol). The resulting solution wasstirred at room temperature overnight. The reaction mixture waspartitioned between ethyl acetate and water. The organic portion wasdried (MgSO₄), filtered and concentrated to dryness. The crude productwas purified by silica gel chromatography eluting with 0-100% ethylacetate/hexanes to yield a white solid (2.0 g, 41%); mp 108-112° C.; ¹HNMR (400 MHz, CDCl₃) δ 9.02 (d, J=2.2 Hz, 1H), 8.51 (t, J=8.7 Hz, 1H),8.37 (s, 1H), 8.30 (s, 1H), 7.98 (ddd, J=8.3, 2.4, 1.3 Hz, 1H), 7.68 (s,1H), 7.36 (dd, J=8.2, 4.8 Hz, 1H), 1.52 (s, 9H); ESIMS m/z 261 ([M+1]).

Compounds 64 and 130 were prepared in accordance with the proceduresdisclosed in Example 13, Method A.

Method B:

To a solution of 1-(pyridin-3-yl)-1H-pyrazol-4-amine (0.1 g, 0.624 mmol)and di-tert-butyl dicarbonate (0.161 mL, 0.693 mmol) in tetrahydrofuran(1.890 mL) and water (0.568 mL) was added dropwise saturated aqueoussodium bicarbonate (0.572 mL, 0.687 mmol). The reaction was stirred atroom temperature overnight. The reaction was diluted with water andextracted with ethyl acetate. The combined organic phases wereconcentrate to give tert-butyl 1-(pyridin-3-yl)-1H-pyrazol-4-ylcarbamate(135 mg, 0.519 mmol, 83%), for which the analytical data was consistentwith that reported in Example 13, Method A.

Compounds 150, 172, 223, and 317 were prepared in accordance with theprocedures disclosed in Example 13, Method B. Compound 172 and 317 wasalso prepared in accordance with the procedures disclosed in Example 17.These compounds, as well as, certain other compounds, were made byalternative methods further illustrating certain embodiments.

Example 14 Preparation of tert-butylmethyl(1-(pyridin-3-yl)-1H-pyrazol-4-yl)carbamate (Compound 67)

To a solution of tert-butyl 1-(pyridin-3-yl)-1H-pyrazol-4-ylcarbamate(1.6 g, 6.15 mmol) in DMF (30.7 mL) at 0° C. was added sodium hydride(0.34 g, 8.61 mmol, 60% dispersion in mineral oil) in one portion andthe suspension was stirred for 30 minutes. The ice bath was removed andstirred for an additional 30 minutes. Iodomethane (0.46 mL, 7.38 mmol)was added in one portion and stirred overnight at room temperature.Water and ethyl acetate were added and the resulting biphasic mixturewas separated. The aqueous layer was extracted one time with ethylacetate. The combined organic extracts were washed with brine, dried(MgSO₄), filtered and concentrated to dryness. The crude product waspurified by silica gel chromatography eluting with 0-35% ethylacetate/hexanes to yield a light yellow semi-solid (0.85 g, 50%): IR(KBr) 1703 cm⁻¹; H NMR (400 MHz, CDCl₃) δ 8.98 (s, 1H), 8.52 (d, J=3.8Hz, 1H), 8.32 (s, 0.5H), 8.13-7.97 (m, 1H), 7.84 (s, 0.5H), 7.74 (s,1H), 7.39 (dd, J=8.0, 4.8 Hz, 1H), 3.30 (s, 3H), 1.56 (s, 9H); ESIMS m/z275 ([M+H]).

Compounds 68, 86-92, 105-106, 114-116, 141, 149, 161-162, 199-200, 254,258, 291, 332, 352, 360-361, 380-381, 414, 430-431, 450, 457, 474-475,485, 488, 510-511, 515, 523, and 590 were prepared from the appropriateamides in accordance with the procedures disclosed in Example 14.

Tert-butyl methyl(3-methyl-1-(pyridin-3-yl)-1H-pyrazol-4-yl)carbamatewas prepared as in Example 14: ¹H NMR (400 MHz, CDCl₃) δ 8.91 (d, J=2.5Hz, 1H), 8.51 (dd, J=4.7, 1.3 Hz, 1H), 8.00 (ddd, J=8.3, 2.4, 1.4 Hz,1H), 7.83 (s, 1H), 7.38 (dd, J=8.3, 4.7 Hz, 1H), 3.20 (s, 3H), 2.22 (s,3H), 1.60-1.30 (m, 9H).

Example 15 Preparation ofN-ethyl-N-(1-methyl-3-(pyridin-3-yl)-1H-pyrazol-5-yl)isobutyramide(Compound 23)

To a solution ofN-(1-methyl-3-(pyridine-3-yl)-1H-pyrazol-5-yl)isobutyramide (0.08 g,0.33 mmol) in DMF (0.66 mL) at 0° C. was added sodium hydride (0.016 g,0.39 mmol, 60% dispersion in mineral oil) in one portion and thesuspension was stirred for 30 minutes. The ice bath was removed andstirred for an additional 30 minutes. Iodoethane (0.06 g, 0.39 mmol) wasadded in one portion and stirred overnight at room temperature. Waterand ethyl acetate were added and the resulting biphasic mixture wasseparated. The aqueous layer was extracted one time with ethyl acetate.The combined organic extracts were washed with brine, dried (MgSO₄),filtered and concentrated to dryness. The crude product was purified bysilica gel chromatography to give the title compound as a clear oil(27.5 mg, 30%): ¹H NMR (300 MHz, CDCl₃) δ 9.00 (bs, 1H), 8.57 (s, 1H),8.09 (dd, J=7.9 Hz, 1H), 7.34 (dd, 1H), 6.48 (s, 1H), 4.00 (m, 1H), 3.76(s, 3H), 3.36 (m, 1H), 2.33 (m, 1H), 1.17 (t, J=7.1 Hz, 3H), 1.08 (t,J=6.7 Hz, 6H); ESIMS m/z 273 (M+H).

Compound 22 was prepared in accordance with the procedures disclosed inExample 15.

Example 16 Preparation of 5-bromo-1H-pyrazol-4-amine, HBr

A mixture of 4-nitro-1H-pyrazole (10 g, 88 mmol) and 5% palladium onAl₂O₃(1 g) in a mixture of ethanol (150 mL) and 50% aqueous HBr (50 mL)was shaken in a Par apparatus under hydrogen (10 psi) for 36 h. Themixture was filtered and the catalyst washed with ethanol. The filtratewas concentrated in vacuo to give a white solid. This solid wassuspended in 10 mL of ethanol. After swirling the flask for 5 min,diethyl ether was added to complete the crystallization. The solid wasfiltered, was washed with ether and dried under high vacuum to afford5-bromo-1H-pyrazol-4-amine, HBr (18.1 g, 84% yield) as a white solid: mp248° C. dec; ¹H NMR (400 MHz, DMSO-d₆) δ 11.47 (s, 1H), 10.00 (s, 1H),7.79 (s, 1H).

Example 17 Preparation oftert-butyl(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)carbamate (Compound172) Example 17 Step 1: Preparation of 3-chloro-1H-pyrazol-4-aminehydrochloride

Into a 2 L three-necked round bottom flask affixed with an overheadstirrer, a temperature probe, an addition funnel, and a nitrogen inletwere added ethanol (600 mL) and 4-nitro-1H-pyrazole (50.6 g, 447 mmol).To this solution was added, in one portion, conc. HCl (368 mL) (note:rapid exotherm from 15° C. to 39° C.) and the resulting mixture waspurged with nitrogen for 5 minutes. Palladium on alumina (5% w/w) (2.6g, Alfa, black solid) was added to the mixture and stirred at roomtemperature while triethylsilane (208 g, 1789 mmol) was added drop-wiseover 4 h. The reaction, which started to slowly exotherm from 35° C. to55° C. over 2.0 h, was stirred for a total of 16 h and vacuum filteredthrough a plug of Celite® to give a biphasic mixture. The mixture wastransferred to a separatory funnel, the bottom aqueous layer wascollected and rotary evaporated (60° C., 50 mmHg) to dryness with theaid of acetonitrile (3×350 mL). The resulting yellow solid was suspendedin acetonitrile (150 mL) and allowed to stand for 2 h at roomtemperature followed by 1 h at 0° C. in the refrigerator. The solidswere filtered and washed with acetonitrile (100 mL) to afford the titledcompound 3-chloro-1H-pyrazol-4-amine hydrochloride (84 g, 97% yield, 80%purity) as a white solid: mp 190-193° C.; ¹H NMR (400 MHz, DMSO-d₆) δ10.46-10.24 (bs, 2H), 8.03 (s, 0.54H), 7.75 (s, 0.46H), 5.95 (bs, 1H));¹³C-NMR (101 MHz, DMSO) δ 128.24, 125.97, 116.71.

Example 17 Step 2: Preparation oftert-butyl(3-chloro-1H-pyrazol-4-yl)carbamate

Into a 2 L round bottom flask was added 3-chloro-1H-pyrazol-4-aminehydrochloride (100 g, 649 mmol) and THF (500 mL). To this mixture wereadded di-tert-butyldicarbonate (156 g, 714 mmol) followed by sodiumbicarbonate (120 g, 1429 mmol) and water (50.0 ml). The mixture wasstirred for 16 h, diluted with water (500 mL) and ethyl acetate (500 mL)and transferred to a separatory funnel. This gave three layers; bottom-awhite gelatinous precipitate, middle-light yellow aqueous, top-auburnorganic. The phases were separated collecting the white gelatinousprecipitate and the aqueous layer together. The aqueous was extractedwith ethyl acetate (2×200 mL) and the ethyl acetate extracts werecombined, washed with brine (200 mL), dried over anhydrous sodiumsulfate, filtered and rotary evaporated to give an auburn thick oil (160g). The thick oil was suspended in hexane (1000 mL) and stirred at 55°C. for 2 h. This gave a light brown suspension. The mixture was cooledto 0° C. and the solid collected by vacuum filtration and rinsed withhexane (2×10 mL). The sample was air dried to constant mass to afford(3-chloro-1H-pyrazol-4-yl)carbamate (102.97 g, 72% yield, 80% purity) asa light brown solid: mp 137-138° C.; ¹H NMR (400 MHz, CDCl₃) δ 10.69 (s,1H), 7.91 (s, 1H), 1.52 (s, 9H).

Example 17 Step 3: Preparation oftert-butyl(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)carbamate (Compound172)

To a dry 2 L round bottom flask equipped with mechanical stirrer,nitrogen inlet, thermometer, and reflux condenser was charged the3-iodopyridine (113.0 g, 551 mmol), (3-chloro-1H-pyrazol-4-yl)carbamate(100 g, 459 mmol), potassium phosphate (powdered in a mortar and pestle)(195 g, 919 mmol), and copper chloride (3.09, 22.97 mmol). Acetonitrile(1 L) followed by N¹,N²-dimethylethane-1,2-diamine (101 g, 1149 mmol)were added and the mixture was heated to 81° C. for 4 hours. The mixturewas cooled to room temperature and filtered through a bed of Celite®.The filtrate was transferred to a 4 L Erlenmeyer flask equipped withmechanical stirrer and diluted with water until the total volume wasabout 4 L. The mixture was stirred for 30 minutes at room temperatureand the resulting solid was collected by vacuum filtration. The solidwas washed with water and washed with water and oven dried for severaldays in vacuo at 40° C. to a constant weight to givetert-butyl(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)carbamate (117.8 g,87% yield, 80% purity) as a tan solid: mp 140-143° C.; ¹H NMR (400 MHz,CDCl₃) δ 8.96 (s, 1H), 8.53 (dd, J=4.7, 1.2 Hz, 1H), 8.36 (s, 1H), 7.98(ddd, J=8.3, 2.7, 1.4 Hz, 1H), 7.38 (dd, J=8.3, 4.8 Hz, 1H), 6.37 (s,1H), 1.54 (s, 9H); ESIMS (m/z) 338 ([M−t−Bu]⁺), 220 ([M-O-t-Bu]⁻).

Compound 172 was also prepared in accordance with the proceduresdisclosed in Example 13. Compound 317 was prepared in accordance withthe procedures disclosed in Example 17 fromtert-butyl(3-bromo-1H-pyrazol-4-yl)carbamate and also in accordance withthe procedures disclosed in Example 13.

Example 18 Preparation of 3-(3-methyl-1H-pyrazol-1-yl)pyridine and3-(5-methyl-1H-pyrazol-1-yl)pyridine

To a solution of 3-methyl-1H-pyrazole (10.99 g, 134 mmol) inN,N-dimethylformamide (100 ml) at 0° C. was added sodium hydride (3.71g, 154 mmol, 60% dispersion). The reaction was stirred at 0° C. for 2hours. 3-Fluoropyridine (10.0 g, 103 mmol) was added, and the reactionwas stirred at 100° C. overnight. The reaction was cooled to roomtemperature and water was added slowly. The mixture was extracted withdichloromethane and the combined organic phases were washed with brine,concentrated and chromatographed (0-100% ethyl acetate/hexanes) toafford 3-(3-methyl-1H-pyrazol-1-yl)pyridine (8.4 g, 52.77 mmol, 51.2%)and 3-(5-methyl-1H-pyrazol-1-yl)pyridine (1.0 g, 6%). Analytical data ofboth products is consistent with that reported under Example 6, Step 1.

3-(3-Bromo-1H-pyrazol-1-yl)pyridine was prepared from 3-fluoropyridineand 3-bromopyrazole, which was made as in WO2008130021, as describedExample 18: mp 89.5-92.5° C.; ¹H NMR (400 MHz, CDCl₃) δ 8.94 (d, J=2.4Hz, 1H), 8.62-8.49 (m, 1H), 8.03 (ddd, J=8.3, 2.7, 1.4 Hz, 1H), 7.87 (d,J=2.5 Hz, 1H), 7.42 (dd, J=8.2, 4.7 Hz, 1H), 6.54 (d, J=2.5 Hz, 1H);ESIMS m/z 224 ([M]⁺).

Example 19 Preparation of3-chloro-1-(5-fluoropyridin-3-yl)-1H-pyrazol-4-amine

To a stirred solution of 5-chloro-1H-pyrazol-4-amine, HCl (2 g, 12.99mmol) and cesium carbonate (8.89 g, 27.3 mmol) in DMF (13 mL) was added3,5-difluoropyridine (1.794 g, 15.58 mmol) and the mixture heated at 70°C. for 12 h. The mixture was cooled to room temperature and filtered.The solids were washed with copious amount of ethyl acetate. Thefiltrates was washed with brine, dried over anhydrous MgSO₄ andconcentrated in vacuo to give a brown solid. This solid was dissolved inethyl acetate and the resulting solution was saturated with hexanes toprecipitate 3-chloro-1-(5-fluoropyridin-3-yl)-1H-pyrazol-4-amine (2.31g, 10.32 mmol, 79% yield) as a brown solid: ¹H NMR (400 MHz, DMSO-d₆) δ8.89-8.82 (m, 1H), 8.45 (d, J=2.5 Hz, 1H), 8.07 (d, J=10.4 Hz, 1H), 7.94(s, 1H), 4.51 (s, 2H);

EIMS (m/z) 213 ([M+1]⁺).3-Bromo-1-(5-fluoropyridin-3-yl)-1H-pyrazol-4-amine was prepared fromthe corresponding pyrazole as described in Example 19: mp 164-165° C.;¹H NMR (400 MHz, CDCl₃) δ 8.65 (d, J=1.7 Hz, 1H), 8.36 (d, J=2.5 Hz,1H), 7.76 (dd, J=5.9, 3.6 Hz, 1H), 7.48 (s, 1H), 3.22 (s, 2H). ¹³C NMR(101 MHz, CDCl₃) δ 160.87, 158.30, 135.36, 135.13, 134.39, 134.35,131.16, 123.31, 114.02, 112.77, 112.54; EIMS (m/z) 258 ([M+1]⁺).

Example 20 Preparation of1-(5-fluoropyridin-3-yl)-3-methyl-1H-pyrazol-4-amine

To a solution of 3-fluoro-5-(3-methyl-4-nitro-1H-pyrazol-1-yl)pyridine(3.133 g, 14.10 mmol) in ethanol (28.2 ml) was added ethyl acetate untilall of the starting material went into solution. The solution wasdegassed and 10% palladium on carbon (0.750 g, 0.705 mmol) was added andthe reaction was stirred in a parr hydrogenator at 40 psi for 3 hours.The solution was filtered through celite with ethyl acetate andconcentrated to give1-(5-fluoropyridin-3-yl)-3-methyl-1H-pyrazol-4-amine (2.000 g, 10.41mmol, 73.8%) as a brown solid: mp 136.0-138.0° C.; ¹H NMR (400 MHz,CDCl₃) δ 8.67-8.59 (m, 1H), 8.27 (d, J=2.5 Hz, 1H), 7.73 (dt, J=9.9, 2.3Hz, 1H), 7.45 (s, 1H), 3.01 (s, 2H), 2.28 (s, 3H); EIMS m/z 192.

1-(Pyridin-3-yl)-3-(trifluoromethyl)-1H-pyrazol-4-amine was preparedfrom the appropriate nitropyrazole as described in Example 20: mp112.5-115.0° C.; ¹H NMR (400 MHz, CDCl₃) δ 8.89 (d, J=2.4 Hz, 1H), 8.57(dd, J=4.7, 1.4 Hz, 1H), 8.03 (ddd, J=8.3, 2.7, 1.5 Hz, 1H), 7.56 (d,J=0.7 Hz, 1H), 7.41 (ddd, J=8.3, 4.8, 0.7 Hz, 1H), 3.47-3.31 (m, 2H);EIMS m/z 228.

Example 21 Preparation of 3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-amine

To 3-(3-chloro-4-nitro-1H-pyrazol-1-yl)pyridine (0.95 g, 4.23 mmol) inacetic acid (8.46 mL), ethanol (8.46 mL) and water (4.23 mL) was addediron powder (1.18 g, 21.15 mmol) and the reaction was stirred at roomtemperature for 30 minutes. To this was added carefully 2 M KOH andextracted with ethyl acetate. The ethyl acetate layers were combined,dried (MgSO₄), filtered and concentrated to dryness. The crude materialwas purified by silica gel chromatography (0-10%methanol/dichloromethane) to give the desired product as a white solid(0.66 g, 80%): ¹H NMR (400 MHz, CDCl₃) δ 8.84 (d, J=2.6 Hz, 1H), 8.49(dd, J=4.7, 1.4 Hz, 1H), 7.95 (ddd, J=8.3, 2.7, 1.5 Hz, 1H), 7.53 (s,1H), 7.37 (ddd, J=8.4, 4.7, 0.6 Hz, 1H), 3.17 (bs, 2H).

3-methyl-1-(2-methylpyridin-3-yl)-1H-pyrazol-4-amine was prepared asdescribed in Example 21: ¹H NMR (400 MHz, CDCl₃) δ 8.48 (dd, J=4.8, 1.6Hz, 1H), 7.62 (dd, J=8.0, 1.6 Hz, 1H), 7.23-7.18 (m, 2H), 2.91 (bs, 2H),2.55 (s, 3H), 2.28 (s, 3H); EIMS m/z 188.

3-Phenyl-1-(pyridin-3-yl)-1H-pyrazol-4-amine was prepared from theappropriate nitropyrazole as described in Example 21: IR (thin film)3324 cm⁻¹; H NMR (400 MHz, CDCl₃) δ 8.94 (d, J=2.2 Hz, 1H), 8.47 (dd,J=4.7, 1.4 Hz, 1H), 8.07 (ddd, J=8.3, 2.7, 1.5 Hz, 1H), 7.87-7.80 (m,2H), 7.60 (s, 1H), 7.50-7.44 (m, 2H), 7.40-7.34 (m, 2H), 3.86 (s, 2H);EIMS m/z 236.

3-Chloro-1-(5-fluoropyridin-3-yl)-1H-pyrazol-4-amine was prepared fromthe appropriate nitropyrazole as described in Example 21: mp149.0-151.0° C.; ¹H NMR (400 MHz, CDCl₃) δ 8.65 (d, J=1.6 Hz, 1H), 8.35(d, J=2.4 Hz, 1H), 7.75 (dt, J=9.5, 2.4 Hz, 1H), 7.51 (s, 1H), 3.21 (s,2H); ESIMS m/z 213 ([M]⁺).

3-Bromo-1-(pyridin-3-yl)-1H-pyrazol-4-amine was prepared from theappropriate nitropyrazole as described in Example 21: mp 143.0-146.0°C.; ¹H NMR (400 MHz, CDCl₃) δ 8.85 (d, J=2.4 Hz, 1H), 8.50 (dd, J=4.7,1.4 Hz, 1H), 7.96 (ddd, J=8.3, 2.7, 1.5 Hz, 1H), 7.49 (s, 1H), 7.37(ddd, J=8.4, 4.7, 0.7 Hz, 1H), 3.21 (s, 2H); ESIMS m/z 241 ([M+2]⁺)

Example 22 Preparation oftert-butyl(5-methyl-1-(pyridin-3-yl)-1H-pyrazol-4-yl)carbamate (Compound281)

To a solution of (E)-tert-butyl1-(dimethylamino)-3-oxobut-1-en-2-ylcarbamate (0.59 g, 2.58 mmol) inethanol (2.5 mL) was added 3-hydrazinylpyridine, 2HCl (0.470 g, 2.58mmol). The reaction mixture was stirred at ambient temperature for 16hours. The reaction mixture was concentrated and purified using silicagel chromatography (0-100% ethyl acetate/hexanes) to yield the titlecompound as an orange foam (0.235 g, 30%): IR (thin film) 3268, 2978 and1698 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 8.75 (dd, J=2.5, 0.5 Hz, 1H), 8.62(dd, J=4.8, 1.5 Hz, 1H), 7.82 (ddd, J=8.2, 2.6, 1.5 Hz, 1H), 7.78 (s,1H), 7.43 (ddd, J=8.1, 4.8, 0.6 Hz, 1H), 6.04 (s, 1H), 2.29 (s, 3H),1.52 (s, 9H); ESIMS m/z 275 ([M+H]⁺), 273 ([M−H]⁻).

Example 23 Preparation of tert-butyl1-(5-fluoropyridin-3-yl)-3-methyl-1H-pyrazol-4-ylcarbamate (Compound111) and tert-butyl5-ethoxy-1-(5-fluoropyridin-3-yl)-3-methyl-1H-pyrazol-4-ylcarbamate(Compound 112)

To a solution of 3-fluoro-5-(3-methyl-4-nitro-1H-pyrazol-1-yl)pyridine(3.133 g, 14.10 mmol) in ethanol (28.2 ml) was added ethyl acetate untilall of the starting material went into solution. The solution wasdegassed and 10% palladium on carbon (0.750 g, 0.705 mmol) was added andthe reaction was stirred in a parr hydrogenator at 40 psi for 3 hours.The solution was filtered through celite with ethyl acetate and thesolvent was removed under reduced pressure. The residue was dissolved intetrahydrofuran (32.0 ml) and water (9.61 ml). Di-tert-butyl dicarbonate(2.52 g, 11.55 mmol) was added followed by saturated aqueous sodiumbicarbonate (9.54 ml, 11.45 mmol). The reaction was stirred at roomtemperature overnight, diluted with water and extracted with ethylacetate. The combined organic phases were concentrated andchromatographed (0-100% ethyl acetate/hexanes) to give tert-butyl1-(5-fluoropyridin-3-yl)-3-methyl-1H-pyrazol-4-ylcarbamate (1.673 g,5.72 mmol, 41.0%) as a yellow solid and the tert-butyl5-ethoxy-1-(5-fluoropyridin-3-yl)-3-methyl-1H-pyrazol-4-ylcarbamate(0.250 g, 0.74 mmol, 5.2%) as a brown oil:

Tert-butyl 1-(5-fluoropyridin-3-yl)-3-methyl-1H-pyrazol-4-ylcarbamate(Compound 111): mp 131.5-133.0° C.; ¹H NMR (400 MHz, CDCl₃) δ 8.75 (s,1H), 8.32 (d, J=2.5 Hz, 1H), 8.28 (s, 1H), 7.77 (dt, J=9.7, 2.4 Hz, 1H),6.15 (s, 1H), 2.29 (s, 3H), 1.54 (s, 9H); ESIMS m/z 293 ([M+H]⁺).

Tert-butyl5-ethoxy-1-(5-fluoropyridin-3-yl)-3-methyl-1H-pyrazol-4-ylcarbamate(Compound 112): IR (thin film) 1698 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 8.88(s, 1H), 8.34 (d, J=2.5 Hz, 1H), 7.83 (d, J=9.9 Hz, 1H), 5.99 (s, 1H),4.37 (q, J=7.0 Hz, 2H), 2.17 (s, 3H), 1.50 (s, 9H), 1.37 (t, J=7.1 Hz,3H); ESIMS m/z 337 ([M+H]⁺).

Example 24 Preparation of Bistert-t-butyl(1-(pyridin-3-yl)-1H-pyrazol-4-yl)carbamate (Compound 595)

To a solution of tert-butyl(1-(pyridin-3-yl)-1H-pyrazol-4-yl)carbamate(2.00 g, 7.68 mmol) in dry THF (21.95 mL) at 0° C. was added 60% sodiumhydride (0.33 g, 8.45 mmol) in one portion and stirred at thattemperature for 30 minutes. To this was then added Boc-Anhydride (1.84g, 8.45 mmol) in one portion and stirred for 5 minutes at 0° C. Thewater bath was removed and the reaction was warmed to room temperatureand stirred at additional 30 minutes. The reaction was quenched withwater and extracted with ethyl acetate. The ethyl acetate layers werecombined, dried (MgSO₄), filtered and concentrated to dryness. The crudematerial was purified by silica gel chromatography (0-100% ethylacetate/hexanes) to give the desired product as a white solid (2.0 g,72%): ¹H NMR (400 MHz, CDCl₃) δ 9.12-8.86 (m, 1H), 8.55 (dd, J=4.7, 1.4Hz, 1H), 8.04 (ddd, J=8.3, 2.7, 1.5 Hz, 1H), 8.01 (d, J=0.5 Hz, 1H),7.84-7.65 (m, 1H), 7.41 (ddd, J=8.3, 4.8, 0.7 Hz, 1H), 1.51 (s, 18H).

Example 25 Preparation of 3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-amine(Compound 516)

To tert-butyl(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)carbamate (2 g,6.79 mmol) in dichloromethane (6.79 ml) was added trifluoroacetic acid(6.79 ml) and the mixture was left stirring at room temperature for 2hours. Toluene (12 mL) was added and the reaction was concentrated tonear dryness. The mixture was poured into a separatory funnel containingsaturated aqueous sodium bicarbonated and was extracted withdichloromethane. The combined organic layers were concentrated to give3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-amine (0.954 g, 4.90 mmol, 72.2%)as a white solid: mp 137.9-139.9° C.; ¹H NMR (400 MHz, CDCl₃) δ 8.84 (d,J=2.4 Hz, 1H), 8.50 (dd, J=4.7, 1.4 Hz, 1H), 7.95 (ddd, J=8.3, 2.7, 1.5Hz, 1H), 7.52 (s, 1H), 7.37 (ddd, J=8.4, 4.7, 0.7 Hz, 1H), 3.18 (s, 2H);ESIMS m/z 196 ([M+H]⁺).

Example 26 Preparation ofN-allyl-1-(5-fluoropyridin-3-yl)-3-methyl-1H-pyrazol-4-aminehydrochloride

To a solution of tert-butylallyl(1-(5-fluoropyridin-3-yl)-3-methyl-1H-pyrazol-4-yl)carbamate (908mg, 2.73 mmol) in dioxane (5 mL) was added HCl (1M in ether) (13.65 mL,13.65 mmol) and the mixture stirred at room temperature for 48 h. Theresulting white solid was filtered, washed with ether and dried undervacuum to giveN-allyl-1-(5-fluoropyridin-3-yl)-3-methyl-1H-pyrazol-4-amine, HCl (688mg, 94% yield) as a white solid: mp 189-190° C.; ¹H NMR (400 MHz, CDCl₃)δ 8.79-8.68 (m, 1H), 8.32-8.26 (m, 1H), 8.23 (s, 1H), 7.98-7.86 (m, 1H),5.86-5.68 (m, 1H), 5.28-5.17 (m, 1H), 5.17-5.03 (m, 1H), 3.59 (d, J=6.2Hz, 2H), 2.11 (s, 3H); EIMS (m/z) 233 ([M+1]⁺).

N-Allyl-3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-amine, HCl was preparedas described in Example 26 from tert-butylallyl(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)carbamate: mp 172-174°C.; ¹H NMR (400 MHz, CDCl₃) δ 9.20 (d, J=2.5 Hz, 1H), 8.65 (dd, J=5.3,1.1 Hz, 1H), 8.61 (ddd, J=8.6, 2.5, 1.1 Hz, 1H), 8.24 (s, 1H), 7.93 (dd,J=8.6, 5.3 Hz, 1H), 3.66 (dt, J=5.5, 1.3 Hz, 2H); EIMS (m/z) 235([M+1]⁺).

N-Allyl-3-methyl-1-(pyridin-3-yl)-1H-pyrazol-4-amine, HCl was preparedas described in Example 26 from tert-butylallyl(3-methyl-1-(pyridin-3-yl)-1H-pyrazol-4-yl): mp 195-197° C.; ¹H NMR(400 MHz, DMSO-d₆) δ 9.12 (d, J=2.4 Hz, 1H), 8.58 (dd, J=5.0, 1.2 Hz,1H), 8.48 (s, 1H), 8.43 (d, J=9.7 Hz, 1H), 7.77 (dd, J=8.4, 5.0 Hz, 1H),6.04-5.92 (m, 1H), 5.44 (dd, J=17.2, 1.4 Hz, 1H), 5.32 (d, J=9.4 Hz,1H), 3.81 (d, J=6.2 Hz, 2H); EIMS (m/z) 249 ([M−1]⁺).

3-Bromo-1-(5-fluoropyridin-3-yl)-N-methyl-1H-pyrazol-4-amine, HCl wasprepared as described in Example 26 from tert-butyl3-bromo-1-(5-fluoropyridin-3-yl)-1H-pyrazol-4-yl(methyl)carbamate: mp167-168° C.; ¹H NMR (400 MHz, CDCl₃) δ 8.93 (s, 1H), 8.50 (d, J=2.5 Hz,1H), 8.23 (s, 1H), 8.14 (dt, J=10.4, 2.3 Hz, 1H), 2.73 (s, 3H).

3-Bromo-N-methyl-1-(pyridin-3-yl)-1H-pyrazol-4-amine, HCl was preparedas described in Example 26 fromtert-butyl(3-bromo-1-(pyridin-3-yl)-1H-pyrazol-4-yl)(methyl)carbamate(160 mg, 0.45 mmol) in dioxane (1 mL) was added 4M HCl: mp. 226-228° C.;¹H NMR (400 MHz, DMSO-d₆) δ 9.26-9.06 (d, J=2.6 Hz, 1H), 8.69-8.54 (m,1H), 8.54-8.39 (d, J=8.0 Hz, 1H), 8.33-8.14 (s, 1H), 7.90-7.72 (m, 1H),2.82-2.67 (s, 3H); EIMS (m/z) 253 ([M+1]⁺), 255 ([M+2H]⁺).

3-Bromo-N-ethyl-1-(pyridin-3-yl)-1H-pyrazol-4-amine, HCl was prepared asdescribed in Example 26 from3-bromo-N-ethyl-1-(pyridin-3-yl)-1H-pyrazol-4-amine, HCl: mp 216-217°C.; ¹H NMR (400 MHz, DMSO-d₆) δ 10.66-10.05 (s, 3H), 9.28-9.20 (d, J=2.5Hz, 1H), 8.74-8.67 (m, 1H), 8.67-8.56 (m, 3H), 7.96-7.84 (m, 1H),3.21-3.14 (m, 2H), 1.29-1.22 (m, 3H); EIMS (m/z) 267 ([M+1]⁺).

3-Chloro-N-(2-methoxyethyl)-1-(pyridin-3-yl)-1H-pyrazol-4-amine, HCl wasprepared as described in Example 26 fromtert-butyl(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)(2-methoxyethyl)carbamate,HCl: mp 157-158° C.; ¹H NMR (400 MHz, DMSO) δ 9.22-9.14 (d, J=2.5 Hz,1H), 8.70-8.65 (s, 1H), 8.65-8.59 (m, 1H), 8.38-8.33 (m, 1H), 8.00-7.89(m, 1H), 3.59-3.50 (t, J=5.8 Hz, 2H), 3.32-3.27 (s, 3H), 3.22-3.14 (m,2H); EIMS (m/z) 253 ([M+1]⁺).

Example 27 Preparation of3-chloro-N-ethyl-1-(pyridin-3-yl)-1H-pyrazol-4-amine hydrochloride

Into a 500 mL three-necked round bottom flask equipped with a magneticstir bar was added a solution oftert-butyl(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)(ethyl)carbamate(21 g, 65.1 mmol) in 1,4-dioxane (35 mL). This pale yellow solution wasplaced into an ice bath and cooled to 1° C. A solution of 4M HCl/dioxane(65 mL, 260 mmol) was added in one portion. After stirring for 20minutes, the ice bath was removed and the suspension was stirred furtherat ambient temperature for 16 hours. The reaction was diluted with 200mL of ethyl ether and the solid was filtered and washed with ether andplaced in a vacuum oven at 40° C. for 18 hours. The title compound wasisolated as a pale yellow solid (18.2 g, 95%): ¹H NMR (400 MHz, MeOD) δ9.52 (d, J=2.5 Hz, 1H), 9.17 (s, 1H), 9.14 (ddd, J=8.7, 2.5, 1.1 Hz,1H), 8.93 (ddd, J=5.7, 1.1, 0.6 Hz, 1H), 8.31 (ddd, J=8.7, 5.7, 0.5 Hz,1H), 3.58 (q, J=7.3 Hz, 2H), 1.48 (t, J=7.3 Hz, 3H); ESIMS m/z 223([M+H]⁺).

3-Chloro-N-methyl-1-(pyridin-3-yl)-1H-pyrazole-4-amine, 2HCl wasprepared as described in Example 27: ¹H NMR (400 MHz, MeOD) δ 9.28 (d,J=2.5 Hz, 1H), 8.86 (ddd, J=8.7, 2.5, 1.2 Hz, 1H), 8.79-8.75 (m, 1H),8.62 (s, 1H), 8.19 (ddd, J=8.7, 5.6, 0.5 Hz, 1H), 3.06 (s, 3H); ¹³C NMR(101 MHz, MeOD) δ 141.42, 139.58, 137.76, 134.58, 134.11, 129.33,127.55, 122.14, 35.62); ESIMS m/z 209 ([M+H]⁺).

Example 28 Preparation of 3-(4-nitro-3-phenyl-1H-pyrazol-1-yl)pyridine

To a suspension of phenylboronic acid (0.546 g, 4.47 mmol) in toluene(6.63 ml) was added 3-(3-chloro-4-nitro-1H-pyrazol-1-yl)pyridine (0.335g, 1.492 mmol) followed by ethanol (3.31 ml) and 2 M aqueous potassiumcarbonate (1.492 ml, 2.98 mmol). The solution was degassed by applyingvacuum and then purging with nitrogen (3 times). To the reaction mixturewas added palladium tetrakis (0.086 g, 0.075 mmol) and the flask washeated at 110° C. under nitrogen for 16 hours. The aqueous layer wasremoved and the organic layer was concentrated. The crude product waspurified via silica gel chromatography (0-100% ethyl acetate/hexanes) togive 3-(4-nitro-3-phenyl-1H-pyrazol-1-yl)pyridine (499 mg, 1.874 mmol,80%) as a yellow solid: mp 144.0-146.0° C.; ¹H NMR (400 MHz, CDCl₃) δ9.09 (d, J=2.3 Hz, 1H), 8.82 (s, 1H), 8.71 (dd, J=4.8, 1.4 Hz, 1H), 8.16(ddd, J=8.3, 2.7, 1.5 Hz, 1H), 7.82-7.74 (m, 2H), 7.55-7.48 (m, 4H);EIMS m/z 266.

Example 29 Preparation of5-bromo-1-(pyridin-3-yl)-1H-pyrazol-4-yl(methyl)carbamate (Compound 110)

To tert-butyl methyl(1-(pyridin-3-yl)-1H-pyrazol-4-yl)carbamate (0.200g, 0.729 mmol) in dichloroethane (3.65 ml) was added1-bromopyrrolidine-2,5-dione (0.260 g, 1.458 mmol) and the reaction wasstirred overnight at 50° C. The reaction was concentrated, diluted withdichloromethane, and washed with water and saturated aqueous sodiumthiosulfate. The organic phase was concentrated to give tert-butyl5-bromo-1-(pyridin-3-yl)-1H-pyrazol-4-yl(methyl)carbamate (256 mg, 0.725mmol, 99%) as a brown oil: IR (thin film) 1697 cm⁻¹; ¹H NMR (400 MHz,CDCl₃) δ 8.89 (s, 1H), 8.68 (d, J=4.1 Hz, 1H), 7.93 (ddd, J=8.2, 2.5,1.5 Hz, 1H), 7.69 (s, 1H), 7.46 (dd, J=8.1, 4.8 Hz, 1H), 3.22 (s, 3H),1.44 (s, 9H); ESIMS m/z 352 ([M−H]⁻).

Example 30 Preparation of Bistert-t-butyl(5-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)carbamate(Compound 109)

To Bis tert-t-butyl(1-(pyridin-3-yl)-1H-pyrazol-4-yl)carbamate (1.30 g,3.61 mmol) in acetonitrile (21.22 mL) was added N-chlorosuccinimide(0.96 g, 7.21 mmol) and the reaction was stirred at 45° C. for 48 hours.The reaction was cooled to room temperature and poured into water andextracted with dichloromethane. The dichloromethane layers werecombined, poured through a phase separator to remove water andconcentrated to dryness. The crude material was purified by silica gelchromatography (0-60% ethyl acetate/hexanes) to give the desired productas a yellow solid (0.90 g, 63%): mp 109-115° C.; ¹H NMR (400 MHz, CDCl₃)δ 8.90 (d, J=2.3 Hz, 1H), 8.68 (dd, J=4.8, 1.5 Hz, 1H), 7.94 (ddd,J=8.2, 2.5, 1.5 Hz, 1H), 7.70 (s, 1H), 7.47 (dtd, J=11.0, 5.6, 5.5, 4.8Hz, 1H), 1.49 (s, 18H); ESIMS m/z 395 ([M+H]⁺).

Tert-butyl(5-chloro-3-methyl-1-(pyridin-3-yl)-1H-pyrazol-4-yl)(methyl)carbamatewas prepared from the appropriate pyrazole in dichloroethane as thesolvent as described in Example 30: ESIMS m/z 324 ([M+H]⁺).

Compounds 110 (see also procedure in Example 29) and 146 were preparedfrom the appropriate pyrazoles using N-bromosuccinimide in accordancewith the procedures disclosed in Example 30.

Tert-butyl5-bromo-3-methyl-1-(pyridin-3-yl)-1H-pyrazol-4-yl(methyl)carbamate wasprepared from the appropriate pyrazole in dichloroethane as described inExample 30: ¹H NMR (400 MHz, CDCl₃) δ 8.88 (d, J=2.3 Hz, 1H), 8.69-8.60(m, 1H), 7.96-7.86 (m, 1H), 7.48-7.39 (m, 1H), 3.18 (s, 3H), 2.26 (s,3H), 1.60-1.36 (m, 9H); ESIMS m/z 368 ([M+H]⁺).

Example 31 Preparation of bistert-butyl(5-fluoro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)carbamate (Compound135)

To a solution of bistert-t-butyl(1-(pyridin-3-yl)-1H-pyrazol-4-yl)carbamate (0.075 g, 0.208mmol) in DMF (0.416 ml) and acetonitrile (0.416 ml) was addedSelecfluor® (0.184 g, 0.520 mmol). The reaction was stirred at roomtemperature for one week. The reaction was concentrated, saturatedaqueous ammonium chloride was added and the mixture was extracted withethyl acetate. The combined organic phases were concentrated andchromatographed (0-100% ethyl acetate/hexanes) to give bistert-butyl(5-fluoro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)carbamate (16 mg,0.042 mmol, 20.32%) as an off-white solid: ¹H NMR (400 MHz, CDCl₃) δ8.97 (t, J=2.0 Hz, 1H), 8.61 (dd, J=4.8, 1.4 Hz, 1H), 7.99 (ddt, J=8.3,2.6, 1.3 Hz, 1H), 7.57 (d, J=2.5 Hz, 1H), 7.44 (ddd, J=8.3, 4.8, 0.6 Hz,1H), 1.50 (s, 18H); ESIMS m/z 379 ([M+H]⁺).

Tert-butyl(5-fluoro-3-methyl-1-(pyridin-3-yl)-1H-pyrazol-4-yl)(methyl)carbamatewas prepared as described in Example 31: ¹H NMR (400 MHz, CDCl₃) δ 8.94(s, 1H), 8.57 (d, J=4.2 Hz, 1H), 7.96 (d, J=7.7 Hz, 1H), 7.41 (dd,J=7.9, 4.7 Hz, 1H), 3.17 (s, 3H), 2.23 (s, 3H), 1.58-1.40 (m, 9H); ESIMSm/z 307 ([M+H]⁺).

Example 32 Preparation ofN-cyclopropyl-3-methyl-1-(pyridin-3-yl)-1H-pyrazol-4-amine Example 32Step 1: Preparation of 3-(4-iodo-3-methyl-1H-pyrazol-1-yl)pyridine

To a mixture of 3-(3-methyl-1H-pyrazol-1-yl)pyridine (6.7 g, 42.1 mmol),iodic acid (2.96 g, 16.84 mmol), and diiodine (8.55 g, 33.7 mmol) inacetic acid (60.1 ml) was added concentrated sulfur acid (3.74 ml, 21.04mmol). The reaction mixture heated to 70° C. for 30 minutes. Thereaction mixture was poured onto ice with sodium thiosulfate and wasextracted with diethyl ether. The combined organic phases were washedwith saturated aqueous sodium bicarbonate. The organic phases were thendried with magnesium sulfate, filtered and concentrated in vacuo. Thesolid residue was dissolved in dichloromethane, applied to a 80 g silicagel column, and eluted with 0-80% acetone in hexanes to afford3-(4-iodo-3-methyl-1H-pyrazol-1-yl)pyridine (11.3 g, 35.7 mmol, 85%) asa white solid: mp 131° C.; ¹H NMR (400 MHz, CDCl₃) δ 8.95-8.85 (m, 1H),8.52 (dd, J=4.8, 1.4 Hz, 1H), 8.00-7.94 (m, 1H), 7.91 (s, 1H), 7.38(ddd, J=8.3, 4.8, 0.7 Hz, 1H), 2.34 (s, 3H); EIMS m/z 285.

Example 32 Step 2: Preparation ofN-cyclopropyl-3-methyl-1-(pyridin-3-yl)-1H-pyrazol-4-amine

To a solution of 3-(4-iodo-3-methyl-1H-pyrazol-1-yl)pyridine (2.0 g,7.02 mmol) in dimethylsulfoxide (7.02 ml) was added1-(5,6,7,8-tetrahydroquinolin-8-yl)ethanone (0.246 g, 1.403 mmol),cyclopropanamine (0.486 ml, 7.02 mmol), cesium carbonate (6.86 g, 21.05mmol) and copper(I) bromide (0.101 g, 0.702 mmol). The reaction mixturewas stirred at 35° C. for 2 days. The reaction mixture was diluted withwater and extracted with dichloromethane. The combined organics werewashed with brine, concentrated and chromatographed (0-100% ethylacetate/hexanes) to giveN-cyclopropyl-3-methyl-1-(pyridin-3-yl)-1H-pyrazol-4-amine (269 mg,1.255 mmol, 17.90%) as a yellow solid: mp 104.0-107.0° C.; ¹H NMR (400MHz, CDCl₃) δ 8.89 (dd, J=2.7, 0.5 Hz, 1H), 8.41 (dd, J=4.7, 1.4 Hz,1H), 7.96 (ddd, J=8.3, 2.7, 1.5 Hz, 1H), 7.51 (s, 1H), 7.33 (ddd, J=8.3,4.7, 0.7 Hz, 1H), 3.42 (s, 1H), 2.53-2.42 (m, 1H), 2.22 (s, 3H),0.72-0.65 (m, 2H), 0.60-0.53 (m, 2H); ESIMS m/z 215 ([M+H]⁺).

3-Methyl-N-(3-(methylthio)propyl)-1-(pyridin-3-yl)-1H-pyrazol-4-aminewas prepared as described in Example 32: IR (thin film) 3298 cm⁻¹; H NMR(400 MHz, CDCl₃) δ 8.87 (d, J=2.3 Hz, 1H), 8.40 (dd, J=4.7, 1.4 Hz, 1H),7.93 (ddd, J=8.3, 2.7, 1.5 Hz, 1H), 7.35 (s, 1H), 7.34-7.29 (m, 1H),3.16 (t, J=6.8 Hz, 2H), 2.89 (s, 1H), 2.64 (t, J=7.0 Hz, 2H), 2.25 (s,3H), 2.13 (s, 3H), 1.95 (p, J=6.9 Hz, 2H); ESIMS m/z 263 ([M+H]⁺).

3-Methyl-N-(2-methyl-3-(methylthio)propyl)-1-(pyridin-3-yl)-1H-pyrazol-4-aminewas prepared as described in Example 32: IR (thin film) 3325 cm⁻¹; H NMR(400 MHz, CDCl₃) δ 8.86 (d, J=2.5 Hz, 1H), 8.40 (dd, J=4.7, 1.2 Hz, 1H),7.93 (ddd, J=8.3, 2.7, 1.5 Hz, 1H), 7.35 (s, 1H), 7.32 (ddd, J=8.3, 4.7,0.5 Hz, 1H), 3.12 (dd, J=11.5, 6.1 Hz, 1H), 2.94 (dd, J=11.9, 6.6 Hz,1H), 2.62 (dd, J=12.9, 6.9 Hz, 1H), 2.52 (dd, J=12.9, 6.2 Hz, 1H), 2.26(s, 3H), 2.14 (s, 3H), 2.12-2.02 (m, 1H), 1.11 (d, J=6.8 Hz, 3H); EIMSm/z 276.

Example 33 Preparation oftert-butyl(3-cyclopropyl-1-(5-fluoropyridin-3-yl)-1H-pyrazol-4-yl)carbamate(Compound 434) andtert-butyl(1-(5-fluoropyridin-3-yl)-1H-pyrazol-4-yl)carbamate (Compound489)

To a suspension of 2-cyclopropyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(1.087 g, 6.47 mmol) in toluene (13.69 ml) was addedtert-butyl(3-bromo-1-(5-fluoropyridin-3-yl)-1H-pyrazol-4-yl)carbamate(1.1 g, 3.08 mmol) followed by ethanol (6.84 ml) and 2 M aqueouspotassium carbonate (3.08 mL, 6.16 mmol). The solution was degassed byapplying vacuum and then purging with nitrogen (3 times). To thereaction mixture was added palladium tetrakis (0.178 g, 0.154 mmol) andthe flask was heated at 100° C. under nitrogen for 36 hours. Water (5mL) was added and the mixture was extracted with ethyl acetate. Thecombined organics were concentrated and chromatographed (0-100% ethylacetate/hexanes) to givetert-butyl(3-cyclopropyl-1-(5-fluoropyridin-3-yl)-1H-pyrazol-4-yl)carbamate(705 mg, 2.215 mmol, 71.9% yield) as a yellow solid andtert-butyl(1-(5-fluoropyridin-3-yl)-1H-pyrazol-4-yl)carbamate (242 mg,0.870 mmol, 28.2% yield) as a yellow solid.

tert-Butyl(3-cyclopropyl-1-(5-fluoropyridin-3-yl)-1H-pyrazol-4-yl)carbamate:mp 156.5-158.0; ¹H NMR (400 MHz, CDCl₃) δ 8.73 (s, 1H), 8.30 (d, J=2.5Hz, 1H), 8.27 (s, 1H), 7.76 (dt, J=9.8, 2.4 Hz, 1H), 6.43 (s, 1H), 1.55(s, 9H), 1.01-0.91 (m, 4H); ESIMS m/z 319 ([M+H]⁺).

(1-(5-Fluoropyridin-3-yl)-1H-pyrazol-4-yl)carbamate: mp 121.0-123.0° C.;¹H NMR (300 MHz, CDCl₃) δ 8.78 (s, 1H), 8.37 (s, 1H), 8.28 (s, 1H), 7.81(d, J=9.6 Hz, 1H), 7.59 (s, 1H), 6.44 (s, 1H), 1.53 (s, 9H). ESIMS m/z278 ([M]⁺).

Compounds 340 and 404 were prepared as described in Example 33.

Example 34 Preparation oftert-butyl(3-ethyl-1-(5-fluoropyridin-3-yl)-1H-pyrazol-4-yl)(methyl)carbamate(Compound 408)

To a N₂-purged solution oftert-butyl(1-(5-fluoropyridin-3-yl)-3-vinyl-1H-pyrazol-4-yl)(methyl)carbamate(0.730 g, 2.293 mmol) in methanol (15.29 ml) was added 10% palladium oncarbon (0.036 g, 0.339 mmol). The reaction was purged with hydrogen andrun under 80 psi of hydrogen at room temperature for 60 hours. Thereaction gave less than 20% conversion. The reaction mixture wasfiltered through celite, concentrated, and redissolved in ethyl acetate(4 mL) and transferred to a bomb. The reaction was heated at 50° C. at600 psi of hydrogen for 20 hours. The reaction was only 50% complete.Methanol (1 mL) and 10% palladium on carbon (36 mg) were added, and thereaction was heated at 80° C. at 650 psi of hydrogen for 20 hours. Thereaction was filtered through celite and concentrated to givetert-butyl(3-ethyl-1-(5-fluoropyridin-3-yl)-1H-pyrazol-4-yl)(methyl)carbamate(616 mg, 1.923 mmol, 84% yield) as yellow oil: IR (thin film) 1692 cm⁻¹;H NMR (300 MHz, CDCl₃) δ 8.71 (t, J=1.4 Hz, 1H), 8.35 (d, J=2.6 Hz, 1H),7.83 (dt, J=9.5, 2.3 Hz, 2H), 3.18 (s, 3H), 2.65 (q, J=7.5 Hz, 2H), 1.44(s, 9H), 1.25 (t, J=7.1 Hz, 3H); EIMS m/z 320.

Example 35 Preparation ofN-(1-(5-fluoropyridin-3-yl)-3-formyl-1H-pyrazol-4-yl)isobutyramide(Compound 560)

To a solution ofN-(1-(5-fluoropyridin-3-yl)-3-vinyl-1H-pyrazol-4-yl)isobutyramide (0.706g, 2.57 mmol) in tetrahydrofuran (12.87 ml) and water (12.87 ml) wasadded osmium tetroxide (0.164 ml, 0.026 mmol). After 10 minutes at roomtemperature, sodium periodate (1.101 g, 5.15 mmol) was added in portionsover 3 minutes and the resulting solution was stirred at roomtemperature. After 18 hours, the solution was poured into 10 mL waterand was extracted with 3×10 mL dichloromethane. The combined organiclayers were dried, concentrated and chromatographed (0-100% ethylacetate/hexanes) to giveN-(1-(5-fluoropyridin-3-yl)-3-formyl-1H-pyrazol-4-yl)isobutyramide (626mg, 2.266 mmol, 88% yield) as a yellow solid: mp 140.0-142.0° C.; ¹H NMR(300 MHz, CDCl₃) δ 10.12 (s, 1H), 9.14 (s, 1H), 8.90 (d, J=2.0 Hz, 1H),8.82 (s, 1H), 8.51 (d, J=2.5 Hz, 1H), 7.92 (dt, J=9.2, 2.4 Hz, 1H), 2.65(dt, J=13.8, 6.9 Hz, 1H), 1.31 (d, J=6.9 Hz, 6H); ESIMS m/z 277([M+H]⁺).

Compound 369 was prepared in accordance with the procedures disclosed inExample 35.

Example 36 Preparation ofN-(1-(5-fluoropyridin-3-yl)-3-(hydroxymethyl)-1H-pyrazol-4-yl)isobutyramide(Compound 435) andN-(1-(5-fluoropyridin-3-yl)-1H-pyrazol-4-yl)isobutyramide (Compound 436)

To a solution ofN-(1-(5-fluoropyridin-3-yl)-3-formyl-1H-pyrazol-4-yl)isobutyramide(0.315 g, 1.140 mmol) in methanol (5.70 ml) at 0° C. was added sodiumborohydride (0.086 g, 2.280 mmol). The reaction was stirred at 0° C. for2 hours, and room temperature for 20 hours. 0.5 M HCl was added, thereaction was neutralized with saturated aqueous sodium bicarbonate, andthe mixture was extracted with dichloromethane. The organic phases wereconcentrated and chromatographed (0-100% ethyl acetate/hexanes) to giveN-(1-(5-fluoropyridin-3-yl)-3-(hydroxymethyl)-1H-pyrazol-4-yl)isobutyramide(180 mg, 0.647 mmol, 56.7%) as a white solid andN-(1-(5-fluoropyridin-3-yl)-1H-pyrazol-4-yl)isobutyramide (9 mg, 0.036mmol, 3.18%) as a white solid.

N-(1-(5-fluoropyridin-3-yl)-3-(hydroxymethyl)-1H-pyrazol-4-yl)isobutyramide:mp 144.0-146.0° C.; ¹H NMR (400 MHz, CDCl₃) δ 8.74 (d, J=1.1 Hz, 1H),8.64 (s, 1H), 8.37-8.29 (m, 2H), 7.74 (dt, J=9.5, 2.3 Hz, 1H), 4.95 (d,J=3.0 Hz, 2H), 3.21-3.06 (m, 1H), 2.63-2.48 (m, 1H), 1.26 (d, J=6.9 Hz,6H); ESIMS m/z 279 ([M+H]⁺).

N-(1-(5-fluoropyridin-3-yl)-1H-pyrazol-4-yl)isobutyramide: IR (thinfilm) 1659 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 8.79 (d, J=1.2 Hz, 1H), 8.60(s, 1H), 8.38 (d, J=2.5 Hz, 1H), 7.81 (dt, J=9.5, 2.3 Hz, 1H), 7.68 (s,1H), 7.54 (s, 1H), 2.63-2.51 (m, 1H), 1.28 (d, J=6.9 Hz, 6H); ESIMS m/z249 ([M+H]⁺).

Example 37 Preparation ofN-(3-(chloromethyl)-1-(5-fluoropyridin-3-yl)-1H-pyrazol-4-yl)isobutyramide(Compound 561)

To a solution ofN-(1-(5-fluoropyridin-3-yl)-3-(hydroxymethyl)-1H-pyrazol-4-yl)isobutyramide(0.100 g, 0.359 mmol) in dichloromethane (3.59 ml) was added thionylchloride (0.157 ml, 2.151 mmol). The reaction was stirred at roomtemperature for 2 hours. Saturated aqueous sodium bicarbonate was added,and the mixture was extracted with dichloromethane. The combined organicphases were washed with brine and concentrated to giveN-(3-(chloromethyl)-1-(5-fluoropyridin-3-yl)-1H-pyrazol-4-yl)isobutyramide(100 mg, 0.337 mmol, 94% yield) as a white solid: mp 172.0-177.0° C.; ¹HNMR (400 MHz, CDCl₃) δ 8.79 (s, 1H), 8.67 (s, 1H), 8.40 (s, 1H), 7.80(dt, J=9.4, 2.3 Hz, 1H), 7.42 (s, 1H), 4.77 (s, 2H), 2.63 (hept, J=6.9Hz, 1H), 1.30 (d, J=6.9 Hz, 6H); ESIMS m/z 298 ([M+H]⁺).

Example 38 Preparation ofN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-2-methoxyacetamide(Compound 512) (see also Example 11)

To a solution of 3-chloro-N-ethyl-1-(pyridin-3-yl)-1H-pyrazol-4-amine,2HCl (0.130 g, 0.502 mmol) and in DCM (2.508 ml) was addedN-ethyl-N-isopropylpropan-2-amine (0.257 ml, 1.505 mmol) followed by2-methoxyacetyl chloride (0.109 g, 1.003 mmol) and the reaction mixturewas stirred at ambient temperature for 16 hours. The reaction wasquenched by the addition of saturated sodium bicarbonate. The organiclayer was extracted with DCM. The organic layer was dried over sodiumsulfate, filtered, concentrated and purified using silica gelchromatography (0-100% ethyl acetate/hexanes) to yield the titlecompound as a pale yellow oil (0.12 g, 77%): IR (thin film) 3514, 3091,2978, 1676 cm⁻¹; H NMR (400 MHz, CDCl₃) δ 8.96 (d, J=2.4 Hz, 1H), 8.63(d, J=3.8 Hz, 1H), 8.09-8.03 (m, 1H), 7.99 (s, 1H), 7.47 (dd, J=8.3, 4.8Hz, 1H), 3.88 (s, 2H), 3.77-3.65 (m, 2H), 3.40 (s, 3H), 1.18 (t, J=7.2Hz, 3H); ESIMS m/z 295 ([M+H]⁺).

Compounds 71, 478, 481, 483-484, and 543 were prepared in accordancewith the procedures disclosed in Example 38.

Example 39 Preparation ofN-(3-chloro-1-(5-fluoropyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-2-methyl-3-(methylthio)butanamide(Compound 182) and(Z)—N-(3-chloro-1-(5-fluoropyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-2-methylbut-2-enamide(Compound 183)

To a solution 2-methyl-3-(methylthio)butanoic acid (0.154 g, 1.039 mmol)in dichloromethane (1 mL) at room temperature was added 1 drop ofdimethylformamide. Oxalyl dichloride (0.178 ml, 2.078 mmol) was addeddropwise and the reaction was stirred at room temperature overnight. Thesolvent was removed under reduced pressure. The residue was redissolvedin dichloromethane (1 mL) and the solvent was removed under reducedpressure. The residue was redissolved in dichloromethane (0.5 mL) andthe solution was added to a solution of3-chloro-N-ethyl-1-(5-fluoropyridin-3-yl)-1H-pyrazol-4-amine (0.100 g,0.416 mmol) and 4-dimethylaminopyridine (0.254 g, 2.078 mmol) indichloromethane (1.5 mL) and stirred at room temperature overnight. Thesolvent was removed under reduced pressure and the residue was purify bychromatography (0-100% ethyl acetate/hexanes) to giveN-(3-chloro-1-(5-fluoropyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-2-methyl-3-(methylthio)butanamide(34 mg, 0.092 mmol, 22.06%) as a faint yellow oil and(Z)—N-(3-chloro-1-(5-fluoropyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-2-methylbut-2-enamide(38 mg, 0.118 mmol, 28.3% yield) as a yellow oil.

N-(3-chloro-1-(5-fluoropyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-2-methyl-3-(methylthio)butanamide:IR (thin film) 1633 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 8.79 (d, J=2.0 Hz,0.66H), 8.77 (d, J=2.0 Hz, 0.33H), 8.50 (d, J=2.6 Hz, 0.33H), 8.49 (d,J=2.5 Hz, 0.66H), 8.08 (s, 0.66H), 7.95 (s, 0.33H), 7.92-7.81 (m, 1H),4.03-3.46 (m, 2H), 3.03-2.78 (m, 1H), 2.59-2.33 (m, 1H), 2.04 (s, 2H),2.02 (s, 1H), 1.32 (d, J=6.7 Hz, 1H), 1.27 (d, J=6.2 Hz, 1H), 1.23 (d,J=6.9 Hz, 2H), 1.18-1.12 (m, 5H); ESIMS m/z 371 ([M]⁺).

(Z)—N-(3-chloro-1-(5-fluoropyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-2-methylbut-2-enamide:¹H NMR (400 MHz, CDCl₃) δ 8.73 (d, J=2.0 Hz, 1H), 8.46 (d, J=2.4 Hz,1H), 7.87 (d, J=4.9 Hz, 1H), 7.84 (dt, J=9.2, 2.4 Hz, 1H), 5.93-5.76 (m,1H), 3.73 (q, J=7.1 Hz, 2H), 1.72 (s, 3H), 1.58 (dd, J=6.9, 0.9 Hz, 3H),1.17 (t, J=7.1 Hz, 3H); ESIMS m/z 323 ([M]⁺).

Compounds 70, 180-181, 389-392, 397-398, 405-406, 427-429, 432, 456,482, 521-522, 532-534, 555, and 589 were prepared from the correspondingintermediates and starting materials in accordance with the proceduresdisclosed in Example 39.

Example 40 Preparation ofN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-methyl-2-(methylthio)acetamide(Compound 337)

To an ice cold solution of 2-(methylthio)acetic acid (0.092 g, 0.863mmol) in DCM (2 mL) was added N-ethyl-N-isopropylpropan-2-amine (0.111g, 0.863 mmol) followed by isobutyl chloroformate (0.099 ml, 0.767mmol). Stirring was continued for 10 minutes. Next, the mixed anhydridewas added to a solution of3-chloro-N-methyl-1-(pyridin-3-yl)-1H-pyrazol-4-amine (0.08 g, 0.383mmol) in DCM (0.66 mL) and the reaction mixture was stirred at ambienttemperature for 2 hours. The reaction mixture was concentrated andpurified using reverse phase C-18 column chromatography (0-100%CH₃CN/H₂O) to yield the title compound as a pale yellow oil (0.075 g,66%): ¹H NMR (400 MHz, CDCl₃) δ 8.95 (d, J=2.5 Hz, 1H), 8.62 (dd, J=4.8,1.4 Hz, 1H), 8.13 (s, 1H), 8.04 (ddd, J=8.3, 2.7, 1.4 Hz, 1H), 7.50-7.43(m, 1H), 3.26 (s, 3H), 3.12 (s, 2H), 2.24 (s, 3H); ¹³C NMR (101 MHz,CDCl₃) δ 170.00, 148.61, 140.15, 140.03, 135.68, 126.56, 126.42, 125.33,124.15, 37.16, 34.94, 16.22; ESIMS m/z 297 ([M+H]⁺).

Compounds 335, 336, and 542 were prepared in accordance with theprocedures disclosed in Example 40.

Example 41 Preparation ofN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-2-methyl-3-oxobutanamide(Compound 499)

To a solution of 3-chloro-N-ethyl-1-(pyridin-3-yl)-1H-pyrazol-4-amine,HCl (259 mg, 1 mmol) and ethyl 2-methyl-3-oxobutanoate (144 mg, 1.000mmol) in dioxane (1 mL) was added2,3,4,6,7,8-hexahydro-1H-pyrimido[1,2-a]pyrimidine (181 mg, 1.30 mmol)and the mixture was heated in a microwave (CEM Discover) at 150° C. for1.5 h, with external IR-sensor temperature monitoring from the bottom ofthe vessel. LCMS (ELSD) indicated a 40% conversion to the desiredproduct. The mixture was diluted with ethyl acetate (50 ML) andsaturated aqueous NH₄Cl (15 mL), and the organic phase was separated.The aqueous phase was extracted with ethyl acetate (20 mL) and thecombined organic phase was washed with brine, dried over MgSO₄ andconcentrated in vacuo to give an oily residue. This residue was purifiedon silica gel eluting with mixtures of ethyl acetate and hexanes to giveN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-2-methyl-3-oxobutanamide(37 mg, 11% yield, 96% purity) as a colorless oil: ¹H NMR (400 MHz,CDCl₃) δ 9.02-8.92 (dd, J=2.6, 0.8 Hz, 1H), 8.68-8.60 (dd, J=4.8, 1.5Hz, 1H), 8.09-7.98 (m, 1H), 7.96-7.87 (s, 1H), 3.87-3.58 (d, J=3.0 Hz,2H), 3.49-3.38 (m, 1H), 2.16-2.08 (s, 3H), 1.39-1.32 (d, J=7.0 Hz, 3H),1.22-1.13 (m, 3H); EIMS (m/z) 321 ([M+1]⁺), 319 ([M−1]⁻).

Example 42 Preparation ofN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethylcyclopropanecarboxamide(Compound 538)

To a solution of 3-chloro-N-ethyl-1-(pyridin-3-yl)-1H-pyrazol-4-aminemonohydrochloride (0.10 g, 0.0.38 mmol) in dichloroethane (0.75 ml) wasadded cyclopropanecarboxylic acid (0.03 g, 0.38 mmol) and4-N,N-dimethylaminopyridine (0.14 g, 1.15 mmol) followed by1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.14 g,0.77 mmol). The reaction was stirred at room temperature overnight. Thereaction mixture was concentrated to dryness and the crude product waspurified by reverse phase silica gel chromatography eluting with 0-50%acetonitrile/water to give a white solid (0.03 g, 25%); mp 111-119° C.;¹H NMR (400 MHz, CDCl₃) δ 8.96 (d, J=2.5 Hz, 1H), 8.63-8.59 (m, 1H),8.06 (ddd, J=8.3, 2.6, 1.4 Hz, 1H), 8.01 (s, 1H), 7.46 (dd, J=8.3, 4.7Hz, 1H), 3.73 (q, J=7.2 Hz, 2H), 1.46 (ddd, J=12.6, 8.1, 4.7 Hz, 1H),1.16 (t, J=7.2 Hz, 3H), 1.04 (t, J=3.7 Hz, 2H), 0.71 (dd, J=7.7, 3.0 Hz,2H); ESIMS m/z 291 ([M+H]).

Compounds 69, 516, 524, 546, 558-559, 582-588, 593, and 594 wereprepared from the appropriate acids in accordance with the proceduresdisclosed in Example 42.

Example 43 Preparation ofN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-2-methyl-3-(methylthio)-N-(3-(methylthio)propanoyl)propanamide(Compound 407)

To a solution ofN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-3-(methylthio)propanamide(0.216 g, 0.728 mmol) in DCE (2.91 ml) in a 10 mL vial was added2-methyl-3-(methylthio)propanoyl chloride (0.244 g, 1.601 mmol). Thevial was capped and placed in a Biotage Initiator microwave reactor for3 hours at 100° C., with external IR-sensor temperature monitoring fromthe side of the vessel. The crude mixture was concentrated and purifiedusing reverse phase C-18 column chromatography (0-100%acetonitrile/water) to yield the title compound as a pale yellow oil (67mg, 22%): IR (thin film) 2916 and 1714 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ8.96-8.92 (d, J=2.7 Hz, 1H), 8.64-8.59 (dd, J=4.9, 1.4 Hz, 1H),8.07-7.99 (m, 2H), 7.50-7.40 (dd, J=8.4, 4.8 Hz, 1H), 3.39-3.28 (m, 1H),3.10-2.99 (td, J=7.2, 3.9 Hz, 2H), 2.96-2.86 (dd, J=13.2, 8.7 Hz, 1H),2.86-2.79 (t, J=7.3 Hz, 2H), 2.58-2.48 (dd, J=13.1, 5.8 Hz, 1H),2.14-2.12 (s, 3H), 2.09-2.06 (s, 3H), 1.30-1.26 (d, J=6.9 Hz, 3H); ESIMSm/z 413 ([M+H]⁺).

Compounds 383, 410, 433, 437, 451, 470, 530 and 531 were prepared inaccordance with the procedures disclosed in Example 43.

Example 44 Preparation ofN-[3-chloro-1-(3-pyridyl)pyrazol-4-yl]-2,2-dideuterio-N-ethyl-3-methylsulfanyl-propanamide(Compound 393)

To a 7 mL vial was added3-chloro-N-ethyl-1-(pyridin-3-yl)-1H-pyrazol-4-amine (111 mg, 0.5 mmol),2,2-dideuterio-3-methylsulfanyl-propanoic acid (58.0 mg, 0.475 mmol) andfollowed by DCM (Volume: 2 mL). The solution was stirred at 0° C. Thenthe solution of DCC (0.500 mL, 0.500 mmol, 1.0 M in DCM) was added. Thesolution was allowed to warm up to 25° C. slowly and stirred at 25° C.overnight. White precipitate formed during the reaction. The crudereaction mixture was filtered through a cotton plug and purified bysilica gel chromatography (0-100% EtOAc/hexane) to giveN-[3-chloro-1-(3-pyridyl)pyrazol-4-yl]-2,2-dideuterio-N-ethyl-3-methylsulfanyl-propanamide(97 mg, 0.297 mmol, 59.4% yield) as a colorless oil: ¹H NMR (400 MHz,CDCl₃) δ 8.96 (d, J=2.4 Hz, 1H), 8.63 (dd, J=4.6, 0.9 Hz, 1H), 8.06(ddd, J=8.4, 2.7, 1.4 Hz, 1H), 7.98 (s, 1H), 7.52-7.40 (m, 1H), 3.72 (q,J=7.2 Hz, 2H), 2.78 (s, 2H), 2.06 (s, 3H), 1.17 (t, J=7.2 Hz, 3H); ESIMSm/z 327 ([M+H]⁺); IR (Thin film) 1652 cm⁻¹.

Compounds 394, 396, and 471-473 were prepared from the correspondingintermediates and starting materials in accordance with the proceduresdisclosed in Example 44.

Example 45 Preparation of1-ethyl-3-(3-methyl-1-(pyridin-3-yl)-1H-pyrazol-4-yl)urea (Compound 145)

To a solution of 3-methyl-1-(pyridin-3-yl)-1H-pyrazol-4-amine (0.1 g,0.574 mmol) in DCM (5.74 ml) was added ethyl isocyanate (0.041 g, 0.574mmol) and the reaction mixture was stirred at ambient temperature for 40minutes. The reaction mixture had turned from a clear solution to asuspension with white solid material. The reaction mixture wasconcentrated and purified using silica gel chromatography (0-20%MeOH/DCM) to yield the title compound as a white solid (0.135 g, 95%):mp 197-200° C.; ¹H NMR (400 MHz, CDCl₃) δ 8.94 (d, J=2.3 Hz, 1H),8.48-8.37 (m, 1H), 8.32 (s, 1H), 7.94 (d, J=8.3 Hz, 1H), 7.52 (br s,1H), 7.41-7.25 (m, 1H), 5.79 (br s, 1H), 3.33-3.23 (m, 2H), 2.29 (d,J=2.9 Hz, 3H), 1.16 (dd, J=8.7, 5.7 Hz, 3H); ESIMS m/z 246 ([M+H]⁺), 244([M−H]⁻).

Compounds 169-171, 221-222, 255-257, 278-280, 297-302, 318-322, 334,345, 348, 375-377, 385-387, and 411-413 were prepared in accordance withthe procedures disclosed in Example 45.

1-(3-Chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-3-ethyl-1-methylthiourea(Compound Y2048) was prepared in accordance with the procedure disclosedin Example 45 using DMAP as a base, dioxane as a solvent, and heatingthe reaction in a microwave (CEM Discover®) with external IR-sensortemperature monitoring from the bottom of the vessel at 120° C. for 2hours: white solid; mp 160.0-162.0° C.; ¹H NMR (300 MHz, CDCl₃) δ 8.94(d, J=2.6 Hz, 1H), 8.62 (dd, J=4.8, 1.4 Hz, 1H), 8.05-7.98 (m, 2H), 7.46(dd, J=8.3, 4.7 Hz, 1H), 5.66 (s, 1H), 3.72-3.59 (m, 5H), 1.17 (t, J=7.2Hz, 3H); ESIMS m/z 297 ([M+H]⁺).

Example 46 Preparation of3-butyl-1-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-1-ethylurea(Compound 500)

To a solution of 3-chloro-N-ethyl-1-(pyridin-3-yl)-1H-pyrazol-4-amine,2HCl (0.130 g, 0.502 mmol) in DCE (1.25 ml) was addedN-ethyl-N-isopropylpropane-2-amine (0.21 mL, 1.255 mmol) followed by1-isocyanatobutane (0.109 g, 1.104 mmol) and the reaction mixture wasstirred at ambient temperature for 16 hours. The reaction mixture wasconcentrated and purified using silica gel chromatography (0-20%MeOH/DCM) to yield the title compound as a beige solid (0.131 g, 77%):IR (thin film) 3326, 2959, 2931, 1648 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ8.95 (s, 1H), 8.62 (d, J=4.0 Hz, 1H), 8.08-8.01 (m, 1H), 7.97 (s, 1H),7.46 (dd, J=8.3, 4.7 Hz, 1H), 4.42-4.32 (m, 1H), 3.74-3.61 (m, 2H),3.27-3.15 (m, 2H), 1.49-1.37 (m, 2H), 1.37-1.22 (m, 2H), 1.19-1.12 (m,3H), 0.94-0.84 (m, 3H); ESIMS m/z 322 ([M+H]⁺).

Compounds 479-480, 501-504, 513, 518 and 519 were prepared according toExample 46.

Example 47 Preparation of1-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)imidazolidin-2-one(Compound 374)

To a solution of1-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-3-(2-chloroethyl)urea (0.1g, 0.333 mmol) in THF (6.66 ml) was added sodium hydride (8.00 mg, 0.333mmol) and the reaction mixture was stirred at ambient temperature for 30minutes. The reaction was quenched by the addition of a solution ofsaturated ammonium chloride and the product was extracted with ethylacetate (2×). The combined organic layers were dried over sodiumsulfate, filtered and concentrated. The product was a beige solid whichwas pure and did not need any further purification (63 mg, 72%): mp167-170° C.; ¹H NMR (400 MHz, CDCl₃) δ 8.96 (d, J=2.2 Hz, 1H), 8.56 (dd,J=4.7, 1.4 Hz, 1H), 8.33 (s, 1H), 7.99 (ddd, J=8.3, 2.7, 1.4 Hz, 1H),7.40 (ddd, J=8.3, 4.8, 0.7 Hz, 1H), 5.00 (s, 1H), 4.14-4.07 (m, 2H),3.68-3.58 (m, 2H); ESIMS m/z 264 ([M+H]⁺).

Compound 349 was prepared in accordance with the procedures disclosed inExample 47.

Example 48 Preparation ofS-tert-butyl(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)(ethyl)carbamothioate(Compound 514)

To a solution of 3-chloro-N-ethyl-1-(pyridin-3-yl)-1H-pyrazol-4-amine,2HCl (0.13 g, 0.502 mmol) in DCM (2.508 ml) was addedN-ethyl-N-isopropylpropan-2-amine (0.257 ml, 1.505 mmol) followed byS-tert-butyl carbonochloridothioate (0.153 g, 1.003 mmol). The reactionmixture was stirred at ambient temperature for 16 hours. The reactionwas quenched by the addition of saturated sodium bicarbonate. Theorganic layer was extracted with DCM. The organic layer was dried oversodium sulfate, filtered, concentrated and purified using silica gelcolumn chromatography (0-100% ethyl acetate/hexanes) to yield the titlecompound as a white solid (132 mg, 78%): mp 91-93° C.; ¹H NMR (400 MHz,CDCl₃) δ 8.96 (d, J=2.5 Hz, 1H), 8.60 (dd, J=4.7, 1.4 Hz, 1H), 8.08-8.03(m, 1H), 7.97 (s, 1H), 7.47-7.41 (m, 1H), 3.69 (q, J=7.2 Hz, 2H), 1.47(s, 9H), 1.21-1.13 (m, 3H); ESIMS m/z 339 ([M+H]⁺).

Compounds 333, 338, 339, 346, 368 and 373 were prepared in accordancewith the procedures disclosed in Example 48.

Example 49 Preparation ofN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-2-methyl-3-(methio)propanethioamide(Compound 364)

To a microwave reaction vessel was addedN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-2-methyl-3-(methio)propanamide(0.07 g, 0.22 mmol) in dichloroethane (1.87 mL) and Lawesson's reagent(0.05 g, 0.12 mmol). The vessel was capped and heated in a BiotageInitiator microwave reactor for 15 minutes at 130° C., with externalIR-sensor temperature monitoring from the side of the vessel. Thereaction was concentrated to dryness and the crude material was purifiedby silica gel chromatography (0-80% acetonitrile/water) to give thedesired product as a yellow oil (0.33 g, 44%): IR (thin film) 1436 cm⁻¹;¹H NMR (400 MHz, CDCl₃) δ 8.97 (d, J=2.5 Hz, 1H), 8.77-8.52 (m, 1H),8.11-7.89 (m, 2H), 7.60-7.38 (m, 1H), 4.62 (bs, 1H), 4.02 (bs, 1H),3.21-2.46 (m, 3H), 2.01 (s, 3H), 1.35-1.15 (m, 6H); ESIMS m/z 355([M+H]⁺).

Compounds 372, 438 and 548 were prepared in accordance with theprocedures disclosed in Example 49.

N-methyl-3-(methylthio)propanethioamide was prepared in accordance withthe procedure disclosed in Example 49 and isolated as a clear oil; ¹HNMR (400 MHz, CDCl₃) δ 7.69 (s, 1H), 3.20 (d, J=4.8 Hz, 3H), 2.99-2.88(m, 4H), 2.15 (s, 3H); ESIMS m/z 150 ([M+H]⁺).

Example 50 Preparation ofN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-4,4,4-trifluoro-3-(methylsulfinyl)butanamide(Compound 570)

To a 20 mL vial was addedN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-4,4,4-trifluoro-3-(methylthio)butanamide(82 mg, 0.209 mmol) and hexafluoroisopropanol (1.5 mL). Hydrogenperoxide (0.054 mL, 0.626 mmol, 35% solution in water) was added in oneportion and the solution was stirred at room temperature. After 3 hoursthe reaction was quenched with saturated sodium sulfite solution andextracted with EtOAc (3×20 mL). The combined organic layers were driedover sodium sulfate, concentrated and purified by chromatography (0-10%MeOH/DCM) to giveN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-4,4,4-trifluoro-3-(methylsulfinyl)butanamide (76 mg, 0.186 mmol, 89% yield) as white semi-solid: ¹H NMR(400 MHz, CDCl₃) δ 8.98 (d, J=2.3 Hz, 1H), 8.63 (td, J=4.8, 2.4 Hz, 1H),8.14-8.01 (m, 2H), 7.46 (ddd, J=8.3, 4.8, 0.7 Hz, 1H), 4.26 (dd, J=17.2,8.4 Hz, 1H), 3.89-3.61 (m, 2H), 3.01 (dd, J=17.6, 8.2 Hz, 1H), 2.77 (s,2H), 2.48 (dd, J=17.7, 3.3 Hz, 1H), 1.19 (t, J=7.2 Hz, 3H) (only oneisomer shown); ESIMS m/z 409 ([M+H]⁺); IR (Thin film) 1652 cm⁻¹.

Compound 571 was prepared from the corresponding intermediates andstarting materials in accordance with the procedures disclosed inExample 50.

Example 51 Preparation ofN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-3-(methylsulfinyl)propanamide(Compound 362)

ToN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-3-(methylthio)propanamide(0.08 g, 0.24 mmol) in glacial acetic acid (0.82 mL) was added sodiumperborate tetrahydrate (0.05 g, 0.25 mmol), and the mixture was heatedat 60° C. for 1 hour. The reaction mixture was carefully poured into aseparatory funnel containing saturated aqueous NaHCO₃ resulting in gasevolution. When the gas evolution had ceased, ethyl acetate was addedand the layers were separated. The aqueous layer was extracted twicewith ethyl acetate, and all the organic layers were combined, dried overMgSO₄, filtered and concentrated under reduced pressure. The crudematerial was purified by silica gel chromatography (0-10%methanol/dichloromethane) to give the desired product as a clear oil(0.03 g, 40%): IR (thin film) 1655 cm⁻¹; ¹H NMR (400 MHz, CDC₁₃) δ 8.95(t, J=9.2 Hz, 1H), 8.63 (dd, J=4.7, 1.4 Hz, 1H), 8.20-7.86 (m, 2H),7.59-7.33 (m, 1H), 3.73 (ddt, J=20.5, 13.4, 6.8 Hz, 2H), 3.23-3.06 (m,1H), 2.94-2.81 (m, 1H), 2.74-2.62 (m, 2H), 2.59 (s, 3H), 1.25-1.07 (m,3H); ESIMS m/z 341 ([M+H]⁺).

Compounds 101-102, 218, 328, 330, and 494 were prepared from theappropriate sulfides in accordance with the procedures disclosed inExample 51.

Example 52 Preparation ofN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-3-(methylsulfonyl)propanamide(Compound 363)

ToN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-3-(methylthio)propanamide(0.08 g, 0.25 mmol) in glacial acetic acid (0.85 mL) was added sodiumperborate tetrahydrate (0.11 g, 0.52 mmol), and the mixture was heatedat 60° C. for 1 hour. The reaction mixture was carefully poured into aseparatory funnel containing saturated aqueous NaHCO₃ resulting in gasevolution. When the gas evolution had ceased, ethyl acetate was addedand the layers were separated. The aqueous layer was extracted twicewith ethyl acetate, and all the organic layers were combined, dried overMgSO₄, filtered and concentrated under reduced pressure. The crudeproduct was purified by silica gel column chromatography (0 to 10%methanol/dichloromethane) to give the desired product as a clear oil(0.04, 47%): (thin film) 1661 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 8.95 (t,J=11.5 Hz, 1H), 8.64 (dd, J=4.8, 1.4 Hz, 1H), 8.17-7.96 (m, 2H),7.59-7.39 (m, 1H), 3.73 (d, J=7.0 Hz, 2H), 3.44 (dd, J=22.5, 15.7 Hz,2H), 2.96 (s, 3H), 2.71 (t, J=6.9 Hz, 2H), 1.18 (dd, J=8.8, 5.5 Hz, 3H);ESIMS m/z 357 ([M+H]⁺).

Compounds 103, 104, 219, 329, 331 and 495 were prepared from theappropriate sulfides in accordance with the procedures disclosed inExample 52.

Example 53 Preparation ofN-(3-methyl-1-(3-fluoropyridin-5-yl)-1H-pyrazol-4-yl)N-ethyl-2-methyl-(3-oxido-λ⁴-sulfanylidenecyanamide)(methyl)propanamide(Compound 250)

To a solution ofN-ethyl-N-(1-(5-fluoropyridin-3-yl)-3-methyl-1H-pyrazol-4-yl)-2-methyl-3-(methylthio)propanamide(0.30 g, 0.89 mmol) in dichloromethane (3.57 mL) at 0° C. was addedcyanamide (0.07 g, 1.78 mmol) and iodobenzenediacetate (0.31 g, 0.98mmol) and subsequently stirred at room temperature for 1 hour. Thereaction was concentrated to dryness and the crude material was purifiedby silica gel column chromatography (10% methanol/ethyl acetate) to givethe desired sulfilamine as a light yellow solid (0.28 g, 85%). To asolution of 70% mCPBA (0.25 g, 1.13 mmol) in ethanol (4.19 mL) at 0° C.was added a solution of potassium carbonate (0.31 g, 2.26 mmol) in water(4.19 mL) and stirred for 20 minutes after which a solution ofsulfilamine (0.28 g, 0.75 mmol) in ethanol (4.19 mL) was added in oneportion. The reaction was stirred for 1 hour at 0° C. The excess mCPBAwas quenched with 10% sodium thiosulfite and the reaction wasconcentrated to dryness. The residue was purified by silica gelchromatography (0-10% methanol/dichloromethane) to give the desiredproduct as a clear oil (0.16 g, 56%): IR (thin film) 1649 cm⁻¹; ¹H NMR(400 MHz, CDCl₃) δ 8.80 (dd, J=43.8, 10.1 Hz, 1H), 8.51-8.36 (m, 1H),8.11 (d, J=38.7 Hz, 1H), 7.96-7.77 (m, 1H), 4.32-3.92 (m, 2H), 3.49-3.11(m, 6H), 2.32 (s, 3H), 1.27-1.05 (m, 6H); ESIMS m/z 393 ([M+H]⁺).

Example 54 Preparation ofN-ethyl-4,4,4-trifluoro-3-methoxy-N-(3-methyl-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-3-(trifluoromethyl)butanamide(Compound 276)

To a solution ofN-ethyl-4,4,4-trifluoro-3-hydroxy-N-(3-methyl-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-3-(trifluoromethyl)butanamide(184 mg, 0.448 mmol) in DMF (3 mL) stirring at 0° C. was added sodiumhydride (26.9 mg, 0.673 mmol). The solution was stirred at 0° C. for 0.5hour. Then iodomethane (0.034 mL, 0.538 mmol) was added and ice bath wasremoved and the mixture was stirred at 25° C. overnight. Reaction wasworked up by slow addition of water and further diluted with 20 mL ofwater, then extracted with 4×20 mL of EtOAc. The combined organic layerswere washed with water, dried over Na₂SO₄ and concentrated. Silica Gelchromatography (0-100% EtOAc/hexane) gaveN-ethyl-4,4,4-trifluoro-3-methoxy-N-(3-methyl-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-3-(trifluoromethyl)butanamide(52 mg, 0.123 mmol, 27.3% yield) as a white solid: mp=83-86° C.; ¹H NMR(400 MHz, CDCl₃) δ 8.94 (d, J=2.5 Hz, 1H), 8.59 (dd, J=4.7, 1.3 Hz, 1H),8.01 (ddd, J=8.3, 2.7, 1.5 Hz, 1H), 7.85 (s, 1H), 7.44 (ddd, J=8.3, 4.8,0.6 Hz, 1H), 4.00 (brs, 1H), 3.73 (s, 3H), 3.39 (brs, 1H), 2.86 (s, 2H),2.26 (s, 3H), 1.16 (t, J=7.1 Hz, 3H); ESIMS m/z 425 ([M+H]⁺); IR (Thinfilm) 1664 cm⁻¹.

Compound 327 was prepared from the corresponding intermediates andstarting materials in accordance with the procedures disclosed inExample 54.

Example 55 Step 1: Preparation ofN-(2-((tert-butyldimethylsilyl)oxy)ethyl)-N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-2-methyl-3-(methylthio)propanamide

A solution ofN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-2-methyl-3-(methylthio)propanamide(0.150 g, 0.483 mmol) in N,N-dimethylformamide (2.413 ml) was cooled to0° C. Sodium hydride (0.039 g, 0.965 mmol, 60% dispersion) was added atand the reaction was stirred at 0° C. for 30 minutes.(2-Bromoethoxy)(tert-butyl)dimethylsilane (0.231 g, 0.965 mmol) wasadded, the ice bath was removed, and the reaction was stirred at roomtemperature for 2 hours. The reaction was heated at 65° C. for 1.5 hoursand then cooled to room temperature. Brine was added and the mixture wasextracted with dichloromethane. The combined organic phases wereconcentrated and chromatographed (0-100% ethyl acetate/hexanes) to giveN-(2-((tert-butyldimethylsilyl)oxy)ethyl)-N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-2-methyl-3-(methylthio)propanamide(0.120 g, 0.243 mmol, 50.4%) as an orange oil: IR (thin film) 1669 cm⁻¹;¹H NMR (400 MHz, CDCl₃) δ 8.88 (d, J=2.5 Hz, 1H), 8.55 (dd, J=4.7, 1.4Hz, 1H), 8.05 (s, 1H), 7.98 (ddd, J=8.3, 2.6, 1.4 Hz, 1H), 7.41 (ddd,J=8.4, 4.8, 0.5 Hz, 1H), 4.35-3.06 (m, 4H), 2.86-2.73 (m, 1H), 2.73-2.59(m, 1H), 2.41 (dd, J=12.8, 5.7 Hz, 1H), 1.94 (s, 3H), 1.11 (d, J=6.7 Hz,3H), 0.80 (s, 9H), 0.00 (s, 3H), −0.01 (s, 3H); ESIMS m/z 470 ([M+H]⁺).

Example 55 Step 2: Preparation ofN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-(2-hydroxyethyl)-2-methyl-3-(methylthio)propanamide(Compound 535)

To a solution ofN-(2-((tert-butyldimethylsilyl)oxy)ethyl)-N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-2-methyl-3-(methylthio)propanamide(0.180 g, 0.384 mmol) in tetrahydrofuran (1.54 ml) was addedtetrabutylammonium fluoride (0.201 g, 0.767 mmol) and the reaction wasstirred at room temperature for 2 hours. Brine was added and the mixturewas extracted with ethyl acetate. The combined organic phases wereconcentrated and chromatographed (0-100% water/acetonitrile) to giveN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-(2-hydroxyethyl)-2-methyl-3-(methylthio)propanamideas a white oil (0.081 g, 0.217 mmol, 56.5%): IR (thin film) 3423, 1654cm⁻¹; H NMR (400 MHz, CDCl₃) δ 9.00 (d, J=2.5 Hz, 1H), 8.62 (dd, J=4.7,1.2 Hz, 1H), 8.25 (s, 1H), 8.07 (ddd, J=8.3, 2.4, 1.3 Hz, 1H), 7.47 (dd,J=8.3, 4.7 Hz, 1H), 4.47-3.70 (m, 3H), 3.65-3.09 (m, 2H), 2.91-2.68 (m,2H), 2.48 (dd, J=12.4, 5.0 Hz, 1H), 2.01 (s, 3H), 1.18 (d, J=6.5 Hz,3H); ESIMS m/z 356 ([M+H]⁺).

Example 56 Preparation of2-(N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-2-methyl-3-(methylthio)propanamido)ethylacetate (Compound 547)

To a solution ofN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-(2-hydroxyethyl)-2-methyl-3-(methylthio)propanamide(0.045 g, 0.127 mmol) in dichloromethane (1.27 ml) was addedN,N-dimethylpyridin-4-amine (0.023 g, 0.190 mmol) and triethylamine(0.019 g, 0.190 mmol) followed by acetyl chloride (0.015 g, 0.190 mmol).The reaction was stirred at room temperature overnight. Water was addedand the mixture was extracted with dichloromethane. The combined organicphases were concentrated and chromatographed (0-100% ethylacetate/hexanes) to give2-(N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-2-methyl-3-(methylthio)propanamido)ethylacetate as a yellow oil (0.015 g, 0.034 mmol, 26.8%): IR (thin film)1739, 1669 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 8.97 (d, J=2.3 Hz, 1H), 8.64(dd, J=4.7, 1.4 Hz, 1H), 8.15 (s, 1H), 8.04 (ddd, J=8.3, 2.7, 1.4 Hz,1H), 7.47 (ddd, J=8.3, 4.8, 0.7 Hz, 1H), 4.50-3.40 (m, 4H), 2.84 (dd,J=12.7, 8.9 Hz, 1H), 2.78-2.63 (m, 1H), 2.46 (dd, J=12.7, 5.4 Hz, 1H),2.03 (s, 3H), 2.01 (s, 3H), 1.16 (d, J=6.6 Hz, 3H); ESIMS m/z 398([M+H]⁺).

Example 57 Preparation of 2,2-dideuterio-3-methylsulfanyl-propanoic acid

To a 100 mL round bottom flask was added 3-(methylthio)propanoic acid (3g, 24.96 mmol), followed by D₂O (23 mL) and KOD (8.53 mL, 100 mmol) (40%wt solution in D₂O), the solution was heated to reflux overnight. NMRshowed ca. 95% D at alpha-position. The reaction was cooled down andquenched with concentrated HCl until pH<2. White precipitate appeared inaqueous layer upon acidifying. Reaction mixture was extracted with 3×50mL EtOAc, the combined organic layers were dried over Na₂SO₄,concentrated in vacuo to almost dryness. 100 mL hexane was added and thesolution was concentrated again to give2,2-dideuterio-3-methylsulfanyl-propanoic acid as a colorless oil (2.539g, 20.78 mmol, 83%): IR (Thin film) 3430, 1704 cm⁻¹; H NMR (400 MHz,CDCl₃) δ 2.76 (s, 2H), 2.14 (s, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 178.28,38.14-28.55 (m), 28.55, 15.51; EIMS m/z 122.

2-Deuterio-2-methyl-3-methylsulfanyl-propanoic acid was prepared asdescribed in Example 57 to afford a colorless oil (3.62 g, 26.8 mmol,60.9%): IR (Thin film) 2975, 1701 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ11.39-10.41 (brs, 1H), 2.88-2.79 (d, J=13.3 Hz, 1H), 2.61-2.53 (d,J=13.3 Hz, 1H), 2.16-2.09 (s, 3H), 1.32-1.25 (s, 3H); ¹³C NMR (101 MHz,CDCl₃) δ 181.74, 39.74-39.02 (m), 37.16, 16.50, 16.03; EIMS m/z 135.

Example 58 Preparation of2-methyl-3-(trideuteriomethylsulfanyl)propanoic acid

To a 50 mL round bottom flask was added 3-mercapto-2-methylpropanoicacid (5 g, 41.6 mmol), followed by MeOH (15 mL), the solution wasstirred at 25° C. Potassium hydroxide (5.14 g, 92 mmol) was added slowlyas the reaction is exothermic. Iodomethane-d₃ (6.63 g, 45.8 mmol) wasadded slowly and then the reaction mixture was heated at 65° C.overnight. The reaction was worked up by addition of 2 N HCl until themixture was acidic. It was then extracted with EtOAc (4×50 mL) and thecombined organic layers were dried over Na₂SO₄, concentrated andpurified with flash chromatography, eluted with 0-80% EtOAc/hexane togive 2-methyl-3-(trideuteriomethylsulfanyl)propanoic acid (4.534 g, 33.0mmol, 79%) as colorless oil: IR (Thin film) 3446, 1704 cm⁻¹; H NMR (400MHz, CDCl₃) δ 2.84 (dd, J=13.0, 7.1 Hz, 1H), 2.80-2.66 (m, 1H), 2.57(dd, J=13.0, 6.6 Hz, 1H), 1.30 (d, J=7.0 Hz, 3H); EIMS m/z 137.

Example 59 Preparation of 2-hydroxy-3-(methylthio)propanoic acid

Sodium methanethiolate (4.50 g, 64.2 mmol) was added at 25° C. to asolution of 3-chloro-2-hydroxypropanoic acid (2 g, 16.06 mmol) in MeOH(120 mL). The reaction mixture was heated at reflux for 8 hours, thencooled to 25° C. The precipitate was removed by filtration and thefiltrate was evaporated. The residue was acidified to pH 2 with 2 N HCl,extracted with EtOAc (3×30 mL), combined organic layers were dried withNa₂SO₄, concentrated to give 2-hydroxy-3-(methylthio)propanoic acid as awhite solid, (1.898 g, 13.94 mmol, 87% yield): mp 55-59° C.; IR (Thinfilm) 2927, 1698 cm⁻¹; H NMR (400 MHz, CDCl₃) δ 6.33 (s, 3H), 4.48 (dd,J=6.3, 4.2 Hz, 1H), 3.02 (dd, J=14.2, 4.2 Hz, 1H), 2.90 (dd, J=14.2, 6.3Hz, 1H), 2.20 (s, 3H); EIMS m/z 136.

Example 60 Preparation of 2-methoxy-3-(methylthio)propanoic acid

To a stirred solution of sodium hydride (0.176 g, 4.41 mmol) in DMF (5mL) was added a solution of 2-hydroxy-3-(methylthio)propanoic acid (0.25g, 1.836 mmol) in 1 mL DMF at 25° C. and stirred for 10 min. Vigorousbubbling was observed upon addition of NaH. Then iodomethane (0.126 mL,2.020 mmol) was added and the solution was stirred at 25° C. overnight.The reaction was quenched by addition of 2 N HCl, extracted with 3×10 mLof EtOAc, the combined organic layers were washed with water (2×20 mL),concentrated and purified by column chromatography, eluted with 0-100%EtOAc/hexane, gave 2-methoxy-3-(methylthio)propanoic acid (126 mg, 0.839mmol, 45.7% yield) as colorless oil: H NMR (400 MHz, CDCl₃) δ 9.10 (s,1H), 4.03 (dd, J=6.9, 4.4 Hz, 1H), 3.51 (s, 3H), 2.98-2.93 (m, 1H), 2.86(dd, J=14.1, 6.9 Hz, 1H), 2.21 (s, 3H); EIMS m/z 150.

Example 61 Preparation of 2-(acetylthiomethyl)-3,3,3-trifluoropropanoicacid

To a 50 mL round bottom flask was added 2-(trifluoromethyl)acrylic acid(6 g, 42.8 mmol), followed by thioacetic acid (4.59 ml, 64.3 mmol). Thereaction was slightly exothermic. The mixture was then stirred at 25° C.overnight. NMR showed some starting material (˜30%). One more equiv ofthioacetic acid was added and the mixture was heated at 95° C. for 1hour, then allowed to cool to room temperature. Mixture was purified byvacuum distillation at 2.1-2.5 mm Hg, fraction distilled at 80-85° C.was mostly thioacetic acid, fraction distilled at 100-110° C. was almostpure product, contaminated by a nonpolar impurity (by TLC). It was againpurified by flash chromatography (0-20% MeOH/DCM), to give2-(acetylthiomethyl)-3,3,3-trifluoropropanoic acid (7.78 g, 36.0 mmol,84% yield) as colorless oil, which solidified under high vacuum to givea white solid: mp 28-30° C.; ¹H NMR (400 MHz, CDCl₃) δ 7.52 (brs, 1H),3.44 (dt, J=7.5, 3.5 Hz, 2H), 3.20 (dd, J=14.9, 11.1 Hz, 1H), 2.38 (s,3H); ¹³C NMR (101 MHz, CDCl₃) δ 194.79, 171.14, 123.44 (q, J=281.6 Hz),50.47 (q, J=27.9 Hz), 30.44, 24.69 (q, J=2.6 Hz); ¹⁹F NMR (376 MHz,CDCl₃) δ-67.82.

Example 62 Preparation of 3,3,3-trifluoro-2-(methylthiomethyl)propanoicacid

To a solution of 2-(acetylthiomethyl)-3,3,3-trifluoropropanoic acid (649mg, 3 mmol) in MeOH (5 mL) stirring at 25° C. was added pellets ofpotassium hydroxide (421 mg, 7.50 mmol) in four portions over 5 minutes.Reaction was exothermic. Then MeI was added in once, the reactionmixture was then heated at 65° C. for 18 hours. The reaction was thencooled down and quenched with 2N HCl until acidic, and the aqueous layerextracted with chloroform (4×20 mL). Combined organic layer was dried,concentrated in vacuo, purified with flash chromatography (0-20%MeOH/DCM), to give 3,3,3-trifluoro-2-(methylthiomethyl)propanoic acid(410 mg, 2.179 mmol, 72.6% yield) as a light yellow oil: ¹H NMR (400MHz, CDCl₃) δ 10.95 (s, 1H), 3.49-3.37 (m, 1H), 3.02 (dd, J=13.8, 10.8Hz, 1H), 2.90 (dd, J=13.8, 4.0 Hz, 1H), 2.18 (s, 3H); ¹³C NMR (101 MHz,CDCl₃) δ 172.04 (q, J=2.8 Hz), 123.55 (q, J=281.2 Hz), 50.89 (q, J=27.5Hz), 29.62 (q, J=2.3 Hz), 15.85; ¹⁹F NMR (376 MHz, CDCl₃) δ-67.98.

Example 63 Preparation of 3-(methylthio)pentanoic acid

S,S-dimethyl carbonodithioate (1.467 g, 12.00 mmol) was added withvigorous stirring to a solution of (E)-pent-2-enoic acid (2.002 g, 20mmol) in 30% KOH solution (prepared from potassium hydroxide (3.87 g, 69mmol) and Water (10 mL)). The reaction mixture was slowly heated to 90°C. over a period of 20-30 min. Heating was continued for 3 hours beforethe reaction was cooled down to 25° C. and quenched slowly with HCl. Themixture was then extracted with DCM (3×30 mL), combined organic layerdried and concentrated to give 3-(methylthio)pentanoic acid (2.7 g,18.22 mmol, 91% yield) as light orange oil: IR (Thin film) 2975, 1701cm⁻¹; H NMR (400 MHz, CDCl₃) δ 2.92 (qd, J=7.3, 5.6 Hz, 1H), 2.63 (d,J=7.2 Hz, 2H), 2.08 (s, 3H), 1.75-1.51 (m, 2H), 1.03 (t, J=7.4 Hz, 3H);¹³C NMR (101 MHz, CDCl₃) δ 178.14, 43.95, 39.78, 27.04, 12.95, 11.29;EIMS m/z 148.

4-methyl-3-(methylthio)pentanoic acid was prepared as described inExample 63 and isolated as a colorless oil: IR (Thin film) 2960, 1704cm⁻¹; H NMR (400 MHz, CDCl₃) δ 2.88 (ddd, J=9.1, 5.4, 4.7 Hz, 1H), 2.68(dd, J=16.0, 5.5 Hz, 1H), 2.55 (dd, J=16.0, 9.1 Hz, 1H), 2.13 (s, 3H),2.01-1.90 (m, 1H), 1.03 (d, J=6.8 Hz, 3H), 0.99 (d, J=6.8 Hz, 3H); EIMSm/z 162.

3-(Methylthio)hexanoic acid was prepared according to the proceduredescribed in Example 63 and isolated as a colorless oil: IR (thin film)2921, 1705 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 10.72 (s, 1H), 3.06-2.92 (m,1H), 2.63 (dd, J=7.2, 2.6 Hz, 2H), 2.08 (s, 3H), 1.66-1.37 (m, 4H), 0.94(t, J=7.2 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 178.19, 42.00, 40.20,36.33, 20.05, 13.80, 12.86.

3-(Cyclopentylthio)-4,4,4-trifluorobutanoic acid was prepared accordingto the procedure described in Example 63 and isolated as a colorlessoil: IR (thin film) 2959, 1714 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 9.27 (s,1H), 3.74-3.53 (m, 1H), 3.36 (p, J=6.9 Hz, 1H), 2.96 (dd, J=16.9, 3.9Hz, 1H), 2.61 (dd, J=16.9, 10.6 Hz, 1H), 2.15-1.92 (m, 2H), 1.84-1.68(m, 2H), 1.68-1.54 (m, 3H), 1.53-1.43 (m, 1H); EIMS m/z 242.

3-Cyclopropyl-3-(methylthio)propanoic acid was prepared according to theprocedure described in Example 63 and isolated as a colorless oil: IR(thin film) 3002, 1703 cm⁻¹; H NMR (400 MHz, CDCl₃) δ 2.73 (dd, J=7.1,2.2 Hz, 2H), 2.39 (dt, J=9.7, 7.1 Hz, 1H), 2.17 (s, 3H), 0.97 (dddd,J=14.6, 13.0, 6.5, 3.6 Hz, 1H), 0.74-0.52 (m, 2H), 0.43-0.35 (m, 1H),0.35-0.26 (m, 1H); ¹³C NMR (101 MHz, CDCl₃) δ 177.60, 47.18, 40.66,16.34, 13.61, 5.30, 4.91.

5-Methyl-3-(methylthio)hexanoic acid was prepared according to theprocedure described in Example 63 and isolated as a light orange oil: IR(thin film) 2955, 1705 cm⁻¹; H NMR (400 MHz, CDCl₃) δ 3.12-2.96 (m, 1H),2.70-2.53 (m, 2H), 2.07 (s, 3H), 1.91-1.78 (m, 1H), 1.49 (ddd, J=14.6,9.1, 5.6 Hz, 1H), 1.38 (ddd, J=14.1, 8.4, 5.9 Hz, 1H), 0.93 (d, J=2.4Hz, 3H), 0.92 (d, J=2.3 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 178.07,43.35, 40.53, 39.99, 25.45, 22.91, 21.83, 12.38.

2-(1-(Methylthio)cyclobutyl)acetic acid was prepared according to theprocedure described in Example 63 and isolated as a white crystallinesolid: mp 43-46° C.; IR (thin film) 2955, 1691 cm⁻¹; ¹H NMR (400 MHz,CDCl₃) δ 2.77 (s, 2H), 2.30 (tdd, J=5.4, 3.9, 2.2 Hz, 2H), 2.23-2.13 (m,3H), 2.04 (s, 3H), 2.00-1.89 (m, 1H); ¹³C NMR (101 MHz, CDCl₃) δ 176.84,47.08, 44.08, 33.27, 16.00, 11.72.

3-(Methylthio)-3-phenylpropanoic acid was prepared according to theprocedure described in Example 63 and isolated as a white solid: mp75-77° C.; IR (thin film) 2915, 1704 cm⁻¹; H NMR (400 MHz, CDCl₃) δ7.35-7.29 (m, 4H), 7.29-7.20 (m, 1H), 4.17 (t, J=7.6 Hz, 1H), 2.93 (dd,J=7.6, 3.2 Hz, 2H), 1.91 (s, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 176.98,140.60, 128.61, 127.64, 127.56, 46.19, 40.70, 14.33.

3-(Methylthio)-3-(4-(trifluoromethyl)phenyl)propanoic acid was preparedaccording to the procedure described in Example 63 and isolated as awhite solid: mp 106-108° C.; IR (thin film) 2924, 1708 cm⁻¹; H NMR (400MHz, CDCl₃) δ 7.59 (d, J=8.1 Hz, 2H), 7.45 (d, J=8.1 Hz, 2H), 4.21 (t,J=7.6 Hz, 1H), 2.95 (qd, J=16.3, 7.7 Hz, 2H), 1.92 (s, 3H); EIMS m/z(M−1) 263.

3-(3-Methoxyphenyl)-3-(methylthio)propanoic acid was prepared accordingto the procedure described in Example 63 and isolated as a white solid:mp 61-63° C.; IR (thin film) 2921, 1699 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ7.28-7.17 (m, 1H), 6.94-6.86 (m, 2H), 6.79 (ddd, J=8.3, 2.5, 0.9 Hz,1H), 4.14 (t, J=7.6 Hz, 1H), 3.80 (s, 3H), 2.92 (d, J=8.0 Hz, 2H), 1.92(s, 3H); EIMS m/z 225.

3-(Methylthio)-3-(pyridin-3-yl)propanoic acid was prepared according tothe procedure described in Example 63 and isolated as a whitesemi-solid: IR (thin film) 3349, 1547 cm⁻¹; ¹H NMR (400 MHz, CD₃OD) δ8.54 (dd, J=2.3, 0.8 Hz, 1H), 8.39 (dd, J=4.9, 1.6 Hz, 1H), 7.90 (dt,J=7.9, 2.0 Hz, 1H), 7.41 (ddd, J=8.0, 4.9, 0.8 Hz, 1H), 4.26 (dd, J=9.2,6.5 Hz, 1H), 2.81 (dd, J=14.7, 6.5 Hz, 1H), 2.71 (dd, J=14.8, 9.2 Hz,1H), 1.94 (s, 3H); EIMS m/z 198.

3-(Methylthio)-3-(pyridin-4-yl)propanoic acid was prepared according tothe procedure described in Example 63 and isolated as a white solid: mp187-189° C.; IR (thin film) 1692 cm⁻¹; H NMR (400 MHz, CD₃OD) δ8.57-8.38 (m, 2H), 7.55-7.37 (m, 2H), 4.19 (dd, J=8.2, 7.3 Hz, 1H), 2.93(dd, J=7.7, 2.8 Hz, 2H), 1.94 (s, 3H); EIMS m/z 198.

Example 64 Preparation of ethyl 1-(hydroxymethyl)cyclopropanecarboxylate

A 1M solution of lithium aluminum tri-tert-butoxyhydride intetrahydrofuran (70.90 mL, 70.90 mmol) was added to a stirred solutionof diethyl cyclopropane-1,1′-dicarboxylate (6 g, 32.20 mmol) intetrahydrofuran (129 mL) at 23° C. The resulting solution was heated to65° C. and stirred for 24 h. The cooled reaction mixture was dilutedwith a 10% solution of sodium bisulfate (275 mL) and extracted withethyl acetate. The combined organic layers were dried (MgSO₄), filtered,and concentrated to dryness to give the desired product as a pale yellowoil (4.60, 91%): ¹H NMR (300 MHz, CDCl₃) δ 4.16 (q, J=7 Hz, 2H), 3.62(s, 2H), 2.60 (br s, 1H), 1.22-1.30 (m, 5H), 0.87 (dd, J=7, 4 Hz, 2H).

Example 65 Preparation of ethyl1-((methylsulfonyloxy)methyl)cyclopropanecarboxylate

Triethylamine (5.57 mL, 40.00 mmol) and methanesulfonyl chloride (2.85mL, 36.60 mmol) were sequentially added to a stirred solution of ethyl1-(hydroxymethyl)cyclopropanecarboxylate (4.80 g, 33.30 mmol) indichloromethane (83 mL) at 23° C. The resulting bright yellow solutionwas stirred at 23° C. for 20 h. The reaction mixture was diluted withwater and extracted with dichloromethane. The combined organic layerswere dried (MgSO₄), filtered, and concentrated to dryness to give thedesired product as a brown oil (6.92 g, 94%): ¹H NMR (300 MHz, CDCl₃) δ4.33 (s, 2H), 4.16 (q, J=7 Hz, 2H), 3.08 (s, 3H), 1.43 (dd, J=7, 4 Hz,2H), 1.26 (t, J=7 Hz, 3H), 1.04 (dd, J=7, 4 Hz, 2H).

Example 66 Preparation of ethyl1-(methylthiomethyl)cyclopropanecarboxylate

Sodium methanethiolate (4.36 g, 62.30 mmol) was added to a stirredsolution of ethyl 1-((methylsulfonyloxy)methyl)cyclopropanecarboxylate(6.92 g, 31.10 mmol) in N,N-dimethylformamide (62.30 mL) at 23° C. Theresulting brown suspension was stirred at 23° C. for 18 h. The reactionmixture was diluted with water and extracted with diethyl ether. Thecombined organic layers were dried (MgSO₄), filtered, and concentratedby rotary evaporation to afford the title compound as a brown oil (5.43g, 100%): ¹H NMR (300 MHz, CDCl₃) δ 4.14 (q, J=7 Hz, 2H), 2.83 (s, 2H),2.16 (s, 3H), 1.31 (dd, J=7, 4 Hz, 2H), 1.25 (t, J=7 Hz, 3H), 0.89 (dd,J=7, 4 Hz, 2H).

Example 67 Preparation of 1-(methylthiomethyl)cyclopropanecarboxylicacid

A 50% solution of sodium hydroxide (12.63 mL, 243 mmol) was added to astirred solution of ethyl 1-(methylthiomethyl)cyclopropanecarboxylate(5.43 g, 31.20 mmol) in absolute ethanol (62.30 mL) at 23° C. Theresulting solution was stirred at 23° C. for 20 h. The reaction mixturewas diluted with a 0.5 M solution of sodium hydroxide and washed withdichloromethane. The aqueous layer was acidified to pH≈1 withconcentrated hydrochloric acid and extracted with dichloromethane. Thecombined organic layers were dried (Na₂SO₄), filtered, and concentratedand concentrated to dryness to give the desired product as a light brownoil (2.10 g, 46%): ¹H NMR (300 MHz, CDCl₃) δ 2.82 (s, 2H), 2.17 (s, 3H),1.41 (dd, J=7, 4 Hz, 2H), 0.99 (dd, J=7, 4 Hz, 2H).

Example 68 Preparation of 2,2-dimethyl-3-(methylthio)propanoic acid

2,2-Dimethyl-3-(methylthio)propanoic acid can be prepared asdemonstrated in the literature (reference Musker, W. K.; et al. J. Org.Chem. 1996, 51, 1026-1029). Sodium methanethiolate (1.0 g, 14 mmol, 2.0equiv) was added to a stirred solution of 3-chloro-2,2-dimethylpropanoicacid (1.0 g, 7.2 mmol, 1.0 equiv) in N,N-dimethylformamide (3.7 mL) at0° C. The resulting brown suspension was allowed to warm to 23° C. andstirred for 24 h. The reaction mixture was diluted with a saturatedsolution of sodium bicarbonate (300 mL) and washed with diethyl ether(3×75 mL). The aqueous layer was acidified to pH≈1 with concentratedhydrochloric acid and extracted with diethyl ether (3×75 mL). Thecombined organic layers were dried (sodium sulfate), gravity filtered,and concentrated to afford a colorless oil (1.2 g, 99% crude yield). ¹HNMR (300 MHz, CDCl₃) δ 2.76 (s, 2H), 2.16 (s, 3H), 1.30 (s, 6H).

Example 69 Preparation of 4,4,4-trifluoro-3-(methylthio)butanoic acid

To a 100 mL round bottom flask was added (E)-4,4,4-trifluorobut-2-enoicacid (8 g, 57.1 mmol) and Methanol (24 mL), the solution was stirred ina water bath, then sodium methanethiolate (10.01 g, 143 mmol) was addedin three portions. Vigorous bubbling was observed, the mixture wasstirred at 25° C. overnight, NMR showed no more starting material. Tothe reaction mixture was added 2 N HCl until acidic. The mixture wasextracted with chloroform (5×50 mL), combined organic layer was driedover Na₂SO₄, concentrated in vacuo and further dried under high vacuumuntil there was no weight loss to give4,4,4-trifluoro-3-(methylthio)butanoic acid (10.68 g, 56.8 mmol, 99%yield) as a colorless oil: ¹H NMR (400 MHz, CDCl₃) δ 10.88 (s, 1H), 3.53(dqd, J=10.5, 8.3, 4.0 Hz, 1H), 2.96 (dd, J=16.9, 4.0 Hz, 1H), 2.65 (dd,J=16.9, 10.4 Hz, 1H), 2.29 (s, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 175.78(s), 126.61 (q, J_(C-F)=278.8 Hz), 44.99 (q, J_(C-F)=30.3 Hz), 34.12 (d,J_(C-F)=1.7 Hz), 15.95 (s); EIMS m/z 162.

Example 70 Preparation of 3-methyl-3-methylsulfanyl-butyric acid

3-methyl-3-methylsulfanyl-butyric acid was made using the proceduresdisclosed in J. Chem Soc Perkin 1, 1992, 10, 1215-21).

Example 71 Preparation of 3-methylsulfanyl-butyric acid

3-Methylsulfanyl-butyric acid was made using the procedures disclosed inSynthetic Comm., 1985, 15 (7), 623-32.

Example 72 Preparation of tetrahydro-thiophene-3-carboxylic acid

Tetrahydro-thiophene-3-carboxylic acid was made using the proceduresdisclosed in Heterocycles, 2007, 74, 397-409.

Example 73 Preparation of 2-methyl-3-methylsulfanyl-butyric acid

2-Methyl-3-methylsulfanyl-butyric acid was made as described in J. ChemSoc Perkin 1, 1992, 10, 1215-21.

Example 74 Preparation of (1S,2S)-2-(methylthio)cyclopropanecarboxylicacid

(1S,2S)-2-(Methylthio)cyclopropanecarboxylic acid was made using theprocedures disclosed in Synthetic Comm., 2003, 33 (5); 801-807.

Example 75 Preparation of 2-(2-(methylthio)ethoxy)propanoic acid

2-(2-(Methylthio)ethoxy)propanoic acid was made as described in WO2007/064316 A1.

Example 76 Preparation of 2-((tetrahydrofuran-3-yl)oxy)propanoic acid

2-((Tetrahydrofuran-3-yl)oxy)propanoic acid was made as described in WO2007/064316 A1.

Example 77 Preparation of tert-Butyl1-(5-fluoropyridin-3-yl)-3-methyl-1H-pyrazol-4-yl(prop-2-ynyl)carbamate(Compound 601)

To an ice cold solution of tert-butyl1-(5-fluoropyridin-3-yl)-3-methyl-1H-pyrazol-4-ylcarbamate (1200 mg,4.11 mmol) in dry DMF (4 mL) under nitrogen was added 60% wt sodiumhydride (197 mg, 4.93 mmol) and the mixture stirred for 10 min.3-Bromoprop-1-yne (733 mg, 6.16 mmol) was then added and the mixture wasstirred for additional 0.5 h at between 0-5° C. The mixture was allowedto warm to ambient temperature and then stirred for additional 3 h atroom temperature. The brown reaction mixture poured into saturatedaqueous NH₄Cl (20 mL), and diluted with ethyl acetate (50 mL). Theorganic phase was separated and the aqueous phase extracted with ethylacetate (20 mL). The combined organic phase was washed with brine, driedover anhydrous MgSO₄, filtered, and concentrated in vacuo to give abrown oil. This oil was purified on silica gel eluting with mixtures ofhexanes and ethyl acetate to give the title compound as a light yellowsolid (1103 mg, 81%); mp 81-82° C.; ¹H NMR (400 MHz, CDCl₃) δ 8.73 (s,1H), 8.37 (d, J=2.5 Hz, 1H), 7.99 (s, 1H), 7.83 (dt, J=9.5, 2.2 Hz, 1H),4.31 (s, 2H), 2.29 (t, J=2.4 Hz, 1H), 2.27 (s, 3H), 1.45 (s, 8H); ESIMSm/z 229.84 ([M]⁺).

Compounds 596 and 606 were prepared in accordance with the proceduredisclosed in Example 77 from the corresponding amine.

Example 78 Preparation of1-(5-fluoropyridin-3-yl)-3-methyl-N-(prop-2-ynyl)-1H-pyrazol-4-amine,hydrochloride

To a solution of tert-butyl1-(5-fluoropyridin-3-yl)-3-methyl-1H-pyrazol-4-yl(prop-2-ynyl)carbamate(1.03 g, 3.11 mmol) in dioxane (5 mL) was added 4M HCl (3.9 mL, 15.5mmol) indioxane. The mixture was stirred at room temperature for 48 hand the resulting white solid was filtered, washed with ether and driedunder vacuum to give to give the title compound as a white solid (741mg, 89%): mp 167-168° C.; ¹H NMR (400 MHz, DMSO d₆) δ 8.92-8.85 (m, 1H),8.42 (d, J=2.5 Hz, 1H), 8.15 (s, 1H), 8.12-8.02 (m, 1H), 3.85 (d, J=2.5Hz, 2H), 3.27-3.19 (m, 1H), 2.22 (s, 3H); ESIMS m/z 230.4 ([M]⁺).3-Chloro-N-(prop-2-ynyl)-1-(pyridin-3-yl)-1H-pyrazol-4-amine,hydrochloride was prepared in accordance with the procedure disclosed inExample 78 from (Compound 606): mp 180-182° C.; ¹H NMR (400 MHz, CDCl₃)δ 9.22 (d, J=2.5 Hz, 1H), 8.67 (dd, J=5.3, 1.0 Hz, 1H), 8.64 (ddd,J=8.6, 2.6, 1.2 Hz, 1H), 8.32 (s, 1H), 7.96 (dd, J=8.6, 5.3 Hz, 1H),3.81 (d, J=2.4 Hz, 2H), 3.15 (t, J=2.4 Hz, 1H); ESIMS m/z 234 ([M+2]⁺).

3-Methyl-N-(prop-2-yn-1-yl)-1-(pyridin-3-yl)-1H-pyrazol-4-amine,hydrochloride was prepared in accordance with the procedure disclosed inExample 78 from Compound 596: mp 161-163° C.; ¹H NMR (400 MHz, DMSO-d₆)δ 8.46 (s, 1H), 8.05 (s, OH), 7.83 (d, J=5.9 Hz, 1H), 7.57 (s, 1H), 7.29(dd, J=8.8, 5.6 Hz, 1H), 3.27 (d, J=2.5 Hz, 2H), 1.52 (s, 3H); EIMS m/z213.1 ([M]⁺).

Example 79 Preparation ofN-(1-(5-Fluoropyridin-3-yl)-3-methyl-1H-pyrazol-4-yl)-3-(methylthio)-N-(prop-2-ynyl)propanamide(Compound 605)

To a stirred solution of1-(5-fluoropyridin-3-yl)-3-methyl-N-(prop-2-yn-1-yl)-1H-pyrazol-4-amine,HCl (100 mg, 0.38 mmol) and N,N-dimethylpyridin-4-amine (115 mg, 0.94mmol) in CH₂Cl₂ (2 mL) was added 2-methyl-3-(methylthio)propanoylchloride (69 mg, 0.45 mmol) and the mixture stirred at room temperaturefor 24 h. The mixture was concentrated in vacuo to give a brown oil,which was purified on silica gel eluting with mixtures of ethyl acetateand hexanes to give the title compound as a colorless oil (80 mg, 61%):¹H NMR (400 MHz, CDCl₃) δ 8.77 (d, J=1.7 Hz, 1H), 8.43 (d, J=2.5 Hz,1H), 8.05 (s, 1H), 7.86 (dt, J=9.4, 2.3 Hz, 1H), 4.49 (s, 1H), 2.88 (dd,J=12.8, 9.4 Hz, 1H), 2.74 (s, 1H), 2.45 (dd, J=12.9, 5.0 Hz, 1H), 2.34(s, 3H), 2.24 (t, J=2.5 Hz, 1H), 2.02 (s, 3H), 1.14 (d, J=6.8 Hz, 3H);ESIMS m/z 347.5 ([M+H]⁺).

Compounds 598, 599, 600, 602, 603, 607, 608 and 610 were prepared inaccordance with the procedure disclosed in Example 79 from thecorresponding amines.

Example 80 Preparation ofN-(3-Chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-4,4,4-trifluoro-3-(methylthio)-N-(prop-2-yn-1-yl)butanamide(Compound 613)

To a 7 mL vial was added3-chloro-N-(prop-2-yn-1-yl)-1-(pyridin-3-yl)-1H-pyrazol-4-amine (140 mg,0.6 mmol), N,N-dimethylpyridin-4-amine (249 mg, 2.040 mmol),N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diaminehydrochloride (276 mg, 1.440 mmol) followed by4,4,4-trifluoro-3-(methylthio)butanoic acid (158 mg, 0.840 mmol) and DCE(1.2 mL). The solution was stirred at 25° C. for 18 hours, the crudereaction mixture was concentrated and purified with silica gelchromatography (0-100% EtOAc/hexane) to give the title compound as abrown oil (237 mg, 0.588 mmol, 98%): (IR thin film) 1674 cm⁻¹; H NMR(400 MHz, CDCl₃) δ 8.97 (d, J=2.6 Hz, 1H), 8.64 (dd, J=4.7, 1.3 Hz, 1H),8.13 (s, 1H), 8.07 (ddd, J=8.3, 2.7, 1.5 Hz, 1H), 7.48 (ddd, J=8.3, 4.8,0.5 Hz, 1H), 4.39 (s, 2H), 3.76 (dqd, J=17.2, 8.6, 3.6 Hz, 1H), 2.67(dd, J=16.6, 3.6 Hz, 1H), 2.46 (dd, J=16.5, 9.9 Hz, 1H), 2.29 (d, J=2.5Hz, 4H); ESIMS m/z 403 ([M+H]⁺).

Compounds 597, 604, 609, 614-616 were prepared in accordance with theprocedure disclosed in Example 80.

Example 81 Preparation of3-Chloro-N-(prop-2-ynyl)-1-(pyridin-3-yl)-1H-pyrazol-4-amine

To a solution oftert-butyl(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)(prop-2-yn-1-yl)carbamate(2.2 g, 6.61 mmol) in dichloromethane (8.3 ml) was added2,2,2-trifluoroacetic acid (12.06 g, 106 mmol) and the reaction mixturewas stirred at ambient temperature for 1 hour. The reaction was quenchedby the addition of saturated sodium bicarbonate. The organic layer wasextracted with dichloromethane (2×20 mL). The organic layers werecombined and dried over sodium sulfate, filtered and concentratedwithout further purification to afford the title compound as a beigesolid (1.5 g, 6.12 mmol, 93%): ¹H NMR (400 MHz, CDCl₃) δ 8.89 (d, J=2.3Hz, 1H), 8.50 (dd, J=4.7, 1.4 Hz, 1H), 8.01-7.93 (m, 1H), 7.54 (s, 1H),7.37 (ddd, J=8.3, 4.8, 0.7 Hz, 1H), 3.90 (s, 2H), 3.38 (s, 1H),2.44-2.09 (m, 1H); ESIMS m/z 233 ([M+H]⁺).

Example 82 Preparation ofN-(3-Chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-2-(methylthio)-N-(prop-2-yn-1-yl)propanamide(Compound 611)

To a solution of 2-(methylthio)propanoic acid (0.36 g, 3.00 mmol) indichloromethane (3 mL) was added oxalyl dichloride (0.29 ml, 3.31 mmol)followed by one drop of N,N-dimethylformamide. The reaction mixture wasstirred for 30 minutes before all solvent was evaporated. The resultingresidue was dissolved in dichloromethane (2 mL) and it was added to apre-stirred solution of3-chloro-N-(prop-2-yn-1-yl)-1-(pyridin-3-yl)-1H-pyrazol-4-amine (0.35 g,1.50 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.57 ml, 3.31 mmol) indichloromethane (5.5 mL). The reaction mixture was stirred at ambienttemperature for 16 hours. The reaction mixture was concentrated and theresidue was purified using silica gel chromatography (0-100% ethylacetate/hexanes) to afford the title compound as a yellow oil (432 mg,1.23 mmol, 85%): ¹H NMR (400 MHz, CDCl₃) δ 8.97 (d, J=2.5 Hz, 1H),8.66-8.60 (m, 1H), 8.25 (s, 1H), 8.08-8.01 (m, 1H), 7.49-7.42 (m, 1H),4.86 (s, 1H), 4.29-3.97 (m, 1H), 3.31 (d, J=6.5 Hz, 1H), 2.30-2.24 (m,1H), 2.09 (s, 3H), 1.46 (d, J=6.9 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ171.30, 148.66, 140.71, 140.18, 135.71, 127.87, 126.35, 124.11, 122.12,78.53, 72.92, 53.39, 37.97, 16.42, 11.07; ESIMS m/z 335 ([M+H]⁺).

Compound 612 was prepared in accordance with the procedure disclosed inExample 82.

Example 83 Preparation ofN-(3-Chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-2-(methylsulfinyl)-N-(prop-2-yn-1-yl)propanamide(Compound 617)

To a solution ofN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-2-(methylthio)-N-(prop-2-yn-1-yl)propanamide(0.1 g, 0.30 mmol) in hexafluoroisoproanol (2.0 ml) was added hydrogenperoxide (35 wt %, 0.08 ml, 0.90 mmol) and the reaction mixture wasstirred vigorously at ambient temperature. The reaction was completeafter 1 hour. The reaction was quenched with saturated sodium sulfitesolution and the organic layer was extracted with ethyl acetate (3×20mL). The combined organic layers were dried over sodium sulfate,filtered and concentrated. The residue was purified using silica gelchromatography (0-20% methanol/dichloromethane) to afford the titlecompound as an off-white foam (82 mg, 0.21 mmol, 78%): ¹H NMR (400 MHz,CDCl₃) δ 8.98 (s, 1H), 8.65 (d, J=4.6 Hz, 1H), 8.23 (s, 1H), 8.11-7.97(m, 1H), 7.51-7.41 (m, 1H), 4.88 (br s, 1H), 4.14 (br s, 1H), 2.64 (s,1.2H), 2.55 (s, 1.8H), 2.33-2.27 (m, 1H), 1.47 (d, J=6.8 Hz, 3H); ¹³CNMR (101 MHz, CDCl₃) δ 168.11, 148.95, 148.78, 140.45, 140.33, 140.20,135.56, 126.54, 124.10, 121.68, 121.58, 121.48, 77.69, 73.49, 38.60;ESIMS m/z 351 ([M+H]⁺).

Example 84 Preparation ofN-(3-Chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-2-(methylsulfonyl)-N-(prop-2-yn-1-yl)propanamide(Compound 618)

To a solution ofN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-2-(methylthio)-N-(prop-2-yn-1-yl)propanamide(0.10 g, 0.30 mmol) and acetic acid (2.0 ml). To this solution was addedsodium perborate tetrahydrate (0.11 g, 0.74 mmol) and the vial washeated to 65° C. for 2 hours. The reaction mixture was cooled to ambienttemperature and neutralized with saturated sodium bicarbonate. Theorganic layer was extracted with ethyl acetate (3×). The organic layerswere combined, dried over sodium sulfate, filtered and concentrated. Theresidue was purified using silica gel chromatography (0-20%methanol/dichloromethane) to afford the title compound as a yellow foam(84 mg, 0.21 mmol, 73%): ¹H NMR (400 MHz, CDCl₃) δ 9.00 (s, 1H), 8.65(s, 1H), 8.29 (s, 1H), 8.03 (d, J=8.0 Hz, 1H), 7.54-7.39 (m, 1H), 4.89(d, J=16.9 Hz, 1H), 4.20-4.08 (m, 1H), 4.07-3.92 (m, 1H), 3.01 (s, 3H),2.34-2.29 (m, 1H), 1.67 (d, J=7.0 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ166.97, 166.90, 148.77, 140.43, 140.24, 135.58, 129.36, 126.64, 124.14,121.34, 73.80, 60.91, 38.78, 36.29, 13.97; ESIMS m/z 367 ([M+H]⁺).

Example 85 Preparation ofN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-2-methyl-3-(tritylthio)propanamide

To a solution of N,N-dimethylpyridin-4-amine (2.60 g, 21.31 mmol),2-methyl-3-(tritylthio)propanoic acid (4.41 g, 12.18 mmol) (preparedaccording to Ondetti, Miguel Angel et. al. DE 2703828) andN1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diaminehydrochloride (2.36 g, 15.22 mmol) in CH₂Cl₂ (20 mL) was added3-chloro-N-ethyl-1-(pyridin-3-yl)-1H-pyrazol-4-amine, 2HCl (3.0 g, 10mmol). The mixture was stirred at 0° C. for 2 hours, then at roomtemperature for additional 48 hours. The mixture was diluted with ethylacetate (100 mL) and saturated aqueous NH₄Cl. The organic phase wasseparated, washed with brine, dried over MgSO₄ and concentrated in vacuoto give a light brown gum. This gum was purified on silica gel elutingwith mixtures of ethyl acetate and hexanes to give the title molecule asa pink solid (2.97 g, 51%): mp 64-66° C.; ¹H NMR (400 MHz, CDCl₃) δ 8.89(d, J=2.7 Hz, 1H), 8.62 (dd, J=4.7, 1.4 Hz, 1H), 7.93-7.86 (m, 1H), 7.82(s, 1H), 7.41 (dd, J=8.3, 4.7 Hz, 1H), 7.33-7.14 (m, 15H), 3.68 (d,J=47.9 Hz, 2H), 2.72 (dd, J=12.0, 8.8 Hz, 1H), 2.37-2.24 (m, 1H), 2.01(dd, J=12.0, 5.2 Hz, 1H), 1.14 (t, J=7.2 Hz, 3H), 0.95 (d, J=6.7 Hz,3H); ESIMS m/z 568 ([M+H]⁺).

Example 86 Preparation ofN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-methyl-3-(tritylthio)propanamide

To a solution of 3-chloro-N-methyl-1-(pyridin-3-yl)-1H-pyrazol-4-amine,HCl (1.5 g, 6.12 mmol) in CH₂Cl₂ (10 mL) were added3-(tritylthio)propanoic acid (2.35 g, 6.73 mmol) (prepared according toOndetti, Miguel Angel et. al. DE 2703828). N,N-dimethylpyridin-4-amine(0.82 g, 6.73 mmol) andN1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine, HCl (1.76g, 9.18 mmol), and the mixture was stirred at room temperature for 16 h.

The mixture was diluted with CH₂Cl₂ (100 mL) and water (50 mL) and theorganic phase separated. The aqueous phase was extracted with ethylacetate and the combined organic phase was washed with brine, dried overMgSO₄ and concentrated in vacuo to give the title molecule as a whitepowder (1.95 g, 59%): mp 62-64° C.; ¹H NMR (400 MHz, CDCl₃) δ 8.91 (d,J=2.7 Hz, 1H), 8.67-8.61 (m, 1H), 8.06-7.96 (m, 1H), 7.81 (s, 1H),7.49-7.46 (m, 1H), 7.25-7.45 (m, 15H), 3.17 (s, 3H), 2.56-2.46 (m, 2H),2.09-1.97 (m, 2H); ESIMS m/z 540 ([M+H]⁺).

Example 87 Preparation ofN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-3-mercapto-N-methylpropanamide

To a solution ofN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-methyl-3-(tritylthio)propanamide(1.300 g, 2.411 mmol) in CH₂Cl₂ (6.14 g, 72.3 mmol) were addedtriethylsilane (1.402 g, 12.06 mmol) followed by 2,2,2-trifluoroaceticacid (2.75 g, 24.11 mmol) at room temperature. The mixture was stirredfor 1 hour and quenched with saturated aqueous NaHCO₃. The mixture wasdiluted with CH₂Cl₂ and the organic phase was separated. The aqueousphase was extracted with CH₂Cl₂ and the organic phases were combined,washed with brine dried over anhydrous MgSO₄ and concentrated in vacuoto give a light yellow oil. This oil was purified on silica gel elutingwith ethyl acetate and hexanes to give the title molecule as a colorlessoil (701 mg, 93%): IR (thin film) 3094, 2980, 1657, 1582 cm⁻¹; ¹H NMR(400 MHz, CDCl₃) δ 8.95 (d, J=2.6 Hz, 1H), 8.63 (s, 1H), 8.06 (s, 1H),8.04-7.96 (m, 1H), 7.52-7.42 (m, 1H), 3.26 (s, 3H), 2.85-2.73 (m, 2H),2.56-2.48 (m, 2H).

The following molecules were made in accordance with the proceduresdisclosed in Example 87:

N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-3-mercatopropanamide

The title molecule was isolated as a light brown gum (902 mg, 64%): IR(thin film) 3086, 2980, 2936, 2548, 1657 cm⁻¹; H NMR (400 MHz, CDCl₃) δ8.96 (dd, J=2.7, 0.7 Hz, 1H), 8.63 (dd, J=4.8, 1.5 Hz, 1H), 8.06 (ddd,J=8.3, 2.7, 1.4 Hz, 1H), 7.97 (s, 1H), 7.47 (ddd, J=8.4, 4.7, 0.8 Hz,1H), 3.72 (q, J=7.1 Hz, 2H), 2.79 (dt, J=8.5, 6.8 Hz, 2H), 2.49 (t,J=6.7 Hz, 2H), 1.67 (t, J=8.4 Hz, 1H), 1.17 (t, J=7.2 Hz, 3H); ESIMS m/z311 ([M+H]⁺), 309 ([M−H]⁻).

N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-3-mercapto-2-methylpropanamide

The title molecule was isolated as a colorless oil which solidified uponstanding: mp 94-96° C.; ¹H NMR (400 MHz, CDCl₃) δ 8.97 (dd, J=2.7, 0.7Hz, 1H), 8.63 (dd, J=4.8, 1.5 Hz, 1H), 8.05 (ddd, J=8.3, 2.7, 1.5 Hz,1H), 8.02 (s, 1H), 7.47 (ddd, J=8.3, 4.8, 0.8 Hz, 1H), 3.85 (m, 1H),3.60 (m, 1H), 2.91 (ddd, J=13.2, 9.4, 8.1 Hz, 1H), 2.41 (ddd, J=13.2,9.2, 4.9 Hz, 1H), 1.49 (dd, J=9.2, 8.2 Hz, 1H), 1.18 (t, J=7.2 Hz, 3H),1.14 (d, J=6.7 Hz, 3H); ESIMS m/z 325 ([M+H]⁺).

Example 88 Preparation of3-(((2,2-difluorocyclopropyl)methyl)thio)propanoic acid

Powdered potassium hydroxide (423 mg, 7.54 mmol) and2-(bromomethyl)-1,1-difluorocyclopropane (657 mg, 3.84 mmol) weresequentially added to a stirred solution of 3-mercaptopropanoic acid(400 mg, 3.77 mmol) in methanol (2 mL) at room temperature. Theresulting white suspension was stirred at 65° C. for 3 h and quenchedwith 1N aqueous HCl and diluted with ethyl acetate. The organic phasewas separated and the aqueous phase extracted with ethyl acetate (2×50mL). The combined organic extracts were dried over MgSO₄, filtered andconcentrated in vacuo to give the title molecule as a colorless oil (652mg, 84%): IR (KBr thin film) 3025, 2927, 2665, 2569, 1696 cm⁻¹; ¹H NMR(400 MHz, CDCl₃) δ 2.85 (t, J=7.0 Hz, 2H), 2.82-2.56 (m, 4H), 1.88-1.72(m, 1H), 1.53 (dddd, J=12.3, 11.2, 7.8, 4.5 Hz, 1H), 1.09 (dtd, J=13.1,7.6, 3.7 Hz, 1H); ESIMS m/z 195.1 ([M−H]⁻).

The following molecules were made in accordance with the proceduresdisclosed in Example 88:4-(((2,2-Difluorocyclopropyl)methyl)thio)butanoic acid: ¹H NMR (400 MHz,CDCl₃) δ 11.31 (s, 1H), 2.71-2.54 (m, 4H), 2.51 (t, J=7.2 Hz, 2H),2.01-1.86 (m, 2H), 1.85-1.70 (m, 1H), 1.51 (dddd, J=12.3, 11.2, 7.8, 4.5Hz, 1H), 1.07 (dtd, J=13.2, 7.6, 3.7 Hz, 1H); ¹³C NMR (101 MHz, CDCl₃) δ179.6, 113.7 (dd, J=286.4, 283.4 Hz), 32.7, 30.7, 28.7 (d, J=4.6 Hz),24.2, 22.8 (t, J=11.2 Hz), 16.6 (t, J=10.8 Hz); ¹⁹F NMR (376 MHz, CDCl₃)δ-128.12 (d, J=156.8 Hz), −142.77 (d, J=156.7 Hz).

4-((2,2,2-Trifluoroethyl)thio)butanoic acid: ¹H NMR (400 MHz, DMSO-d₆) δ3.47 (q, J=10.8 Hz, 2H), 2.72 (dd, J=7.8, 6.6 Hz, 2H), 2.32 (td, J=7.3,4.5 Hz, 2H), 1.96-1.81 (m, 2H).

Example 89 Preparation ofN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-3-(((2,2-difluorocyclopropyl)methyl)thio)-N-ethylpropanamide(Molecule 626)

To a solution ofN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-3-mercatopropanamide(100 mg, 0.322 mmol) in THF (1 mL) was added sodium hydride (60%dispersion in oil, 13.5 mg, 0.34 mmol). The resulting mixture wasstirred at room temperature for 10 min followed by addition of2-(bromomethyl)-1,1-difluorocyclopropane (60 mg, 0.35 mmol). The mixturewas stirred at room temperature for 24 h and diluted with saturatedaqueous ammonium chloride and ethyl acetate. The organic phase wasseparated and the aqueous phase extracted with ethyl acetate (2×50 mL).The combined organic extracts were dried over MgSO₄, filtered andconcentrated in vacuo to give a colorless oil. This oil was purified bychromatography eluting with mixtures of ethyl acetate and hexanes togive the title molecule as a colorless gum (101 mg, 78%): IR (thin film)3092, 2975, 2931, 1659, 1584 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 8.99-8.90(m, 1H), 8.63 (dd, J=4.8, 1.5 Hz, 1H), 8.05 (ddd, J=8.3, 2.7, 1.5 Hz,1H), 7.96 (s, 1H), 7.47 (ddd, J=8.3, 4.7, 0.7 Hz, 1H), 3.72 (q, J=7.2Hz, 2H), 2.87 (t, J=7.3 Hz, 2H), 2.63-2.55 (m, 2H), 2.46 (t, J=7.3 Hz,2H), 1.76 (ddq, J=13.2, 11.4, 7.5 Hz, 1H), 1.48 (dddd, J=12.3, 11.2,7.8, 4.5 Hz, 1H), 1.17 (t, J=7.2 Hz, 3H), 1.04 (dtd, J=13.2, 7.6, 3.7Hz, 1H); ESIMS m/z 400 ([M+H]⁺).

Molecules 624, 625, 629, 633, 643 653 in Table 1 were made in accordancewith the procedures disclosed in Example 89.

Example 90 Preparation ofN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-3-(((2,2-difluorocyclopropyl)methyl)sulfinyl)-N-ethylpropanamide(Molecule 627)

To a solution ofN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-3-(((2,2-difluorocyclopropyl)methyl)thio)-N-ethylpropanamide(100 mg, 0.25 mmol) in acetic acid (5 ml, 0.25 mmol) was added sodiumperborate tetrahydrate (38.4 mg, 0.25 mmol) and the mixture stirred at50° C. for 1 hour. The mixture was cooled to room temperature, quenchedwith saturated aqueous sodium bicarbonate and then diluted with ethylacetate. The organic phase was separated and the aqueous phase extractedwith ethyl acetate. The combined organic phase was washed with brine,dried over MgSO₄ and concentrated in vacuo to give a colorless oil. Thisoil was purified on silica gel eluting with methanol and CH₂Cl₂ (0-10%gradient) to give the title molecule as a colorless gum (91 mg, 88%): IR(thin film) 3448, 3092, 2976, 2933, 1659, 1585, 1440, 1012 cm⁻¹; ¹H NMR(400 MHz, CDCl₃) δ 8.97 (d, J=2.6 Hz, 1H), 8.63 (dd, J=4.8, 1.5 Hz, 1H),8.04 (m, 2H), 7.46 (ddd, J=8.3, 4.8, 0.7 Hz, 1H), 3.72 (dq, J=13.8, 7.0Hz, 2H), 3.16 (ddd, J=20.3, 13.9, 6.8 Hz, 1H), 3.00-2.79 (m, 3H), 2.69(m, 2H), 2.13-1.85 (m, 1H), 1.77-1.62 (m, 1H), 1.41-1.21 (m, 1H), 1.18(t, J=7.2 Hz, 3H); ESIMS m/z 417 ([M+H]⁺).

Molecules 622, 630, 645 in Table 1 were made in accordance with theprocedures disclosed in Example 90.

Example 91 Preparation ofN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-3-(((2,2-difluorocyclopropyl)methyl)sulfonyl)-N-ethylpropanamide (Molecule 628)

To a solution ofN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-3-(((2,2-difluorocyclopropyl)methyl)thio)-N-ethylpropanamide(100 mg, 0.25 mmol) in acetic acid (5 ml, 0.25 mmol) was added sodiumperborate tetrahydrate (77 mg, 0.499 mmol) and the mixture stirred at50° C. for 1 hour. The mixture was cooled to room temperature, quenchedwith saturated aqueous sodium bicarbonate and then diluted with ethylacetate. The organic phase was separated and the aqueous phase wasextracted with ethyl acetate. The combined organic phase was washed withbrine, dried over MgSO₄ and concentrated in vacuo to give a brown oil.This oil was purified on silica gel eluting with mixtures of ethylacetate and hexanes to give the title molecule as a colorless gum (90mg, 83%): IR (thin film) 3104, 2980, 2934, 1662, 1486, 1460 cm⁻¹; H NMR(400 MHz, CDCl₃) δ 9.00-8.90 (m, 1H), 8.64 (dd, J=4.7, 1.4 Hz, 1H),8.09-8.00 (m, 2H), 7.47 (ddd, J=8.4, 4.8, 0.7 Hz, 1H), 3.72 (d, J=7.1Hz, 2H), 3.43 (s, 2H), 3.30 (dd, J=14.7, 6.8 Hz, 1H), 3.11-3.00 (m, 1H),2.72 (t, J=6.9 Hz, 2H), 2.13-1.96 (m, 1H), 1.73 (tdd, J=11.5, 8.3, 5.4Hz, 1H), 1.45 (ddt, J=16.1, 8.0, 3.8 Hz, 1H), 1.18 (t, J=7.2 Hz, 3H);ESIMS m/z 433 ([M+H]⁺).

Molecules 623, 631, 644 in Table 1 were made in accordance with theprocedures disclosed in Example 91.

Example 92 Preparation ofN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-(cyclopropylmethyl)-3-(((2,2-difluorocyclopropyl)methyl)thio)propanamid(Molecule 632)

To a solution of3-chloro-N-(cyclopropylmethyl)-1-(pyridin-3-yl)-1H-pyrazol-4-amine (108mg, 0.43 mmol), N,N-dimethylpyridin-4-amine (53 mg, 0.43 mmol) and3-(((2,2-difluorocyclopropyl)methyl)thio)propanoic acid (85 mg, 0.43mmol) in DMF (5 mL) was addedN1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diaminehydrochloride (101 mg, 0.65 mmol). The resulting brown-yellow mixturewas stirred at ambient temperature for 2 h. The mixture was diluted withsaturated aqueous ammonium chloride and ethyl acetate. The organic phasewas separated and the aqueous phase extracted with ethyl acetate (2×50mL). The combined organic extracts were dried over MgSO₄, filtered andconcentrated in vacuo to give the title molecule as a colorless oil (120mg, 61%): IR (thin film) 3089, 3005, 2923, 1660 1584 cm⁻¹; ¹H NMR (400MHz, CDCl₃) δ 8.95 (d, J=2.6 Hz, 1H), 8.63 (dd, J=4.8, 1.5 Hz, 1H), 8.05(ddd, J=8.3, 2.7, 1.5 Hz, 1H), 7.99 (s, 1H), 7.47 (ddd, J=8.3, 4.7, 0.7Hz, 1H), 3.54 (s, 2H), 2.88 (t, J=7.3 Hz, 2H), 2.69-2.54 (m, 2H), 2.48(t, J=7.3 Hz, 2H), 1.76 (ddt, J=18.7, 13.3, 7.4 Hz, 1H), 1.53-1.42 (m,1H), 1.12-0.90 (m, 2H), 0.54-0.44 (m, 2H), 0.20 (dt, J=6.1, 4.6 Hz, 2H);ESIMS m/z 427 ([M+H]⁺).

Molecule 646 in Table 1 was made in accordance with the proceduresdisclosed in Example 92.

Example 93 Preparation of(E)-N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-4,4,4-trifluorobut-2-enamide

To a solution of 3-chloro-N-ethyl-1-(pyridin-3-yl)-1H-pyrazol-4-amine,2HCl (1.0 g, 3.38 mmol), N,N-dimethylpyridin-4-amine (827 mg, 6.77mmol), and (E)-4,4,4-trifluorobut-2-enoic acid (474 mg, 3.38 mmol) inDMF (3 mL) was addedN1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine, HCl (973mg, 5.07 mmol). The resulting brown-yellow mixture was stirred atambient temperature for 2 hours. The mixture was diluted with saturatedaqueous NH₄Cl and ethyl acetate and saturated with NaCl. The organicphase was separated and the aqueous phase extracted with ethyl; acetate(22×5050 mL). The combined organic phase was dried over MgSO₄, filteredand concentrated in vacuo to give the title molecule as a light browngum (901 mg, 73%): IR (thin film) 3093, 2978, 2937, 1681, 1649, 1585,1114 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 8.97 (d, J=2.7 Hz, 1H), 8.65 (dd,J=4.9, 1.4 Hz, 1H), 8.07 (ddd, J=8.3, 2.7, 1.5 Hz, 1H), 7.99 (s, 1H),7.48 (dd, J=8.3, 4.8 Hz, 1H), 6.84 (dq, J=15.4, 6.8 Hz, 1H), 6.60-6.44(m, 1H), 3.80 (q, J=7.2 Hz, 2H), 1.22 (t, J=7.2 Hz, 3H); ESIMS m/z 345([M+H]⁺).

Example 94 Preparation ofS-(4-((3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)(ethyl)amino)-1,1,1-trifluoro-4-oxobutan-2-yl)ethanethioate

To a solution of(E)-N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-4,4,4-trifluorobut-2-enamide(465 mg, 1.349 mmol) in dry DMSO (5 mL) was added potassiumethanethioacetate (616 mg, 5.40 mmol). The mixture was stirred at 50° C.for 96 hours under nitrogen. The mixture was quenched with saturatedammonium chloride and extracted twice with ethyl acetate. The combinedorganic phase was washed with brine, dried over MgSO₄, filtered andconcentrated in vacuo to give a brown gum. Purification of this gum onsilica gel eluting with mixtures of hexane and ethyl acetate gave thetitle molecule as a brown gum (265 mg, 44%): IR (thin film) 3099, 2976,2936, 1708, 1666, 1585, 1102 cm⁻¹; H NMR (400 MHz, CDCl₃) δ 9.03-8.93(m, 1H), 8.64 (dd, J=4.7, 1.5 Hz, 1H), 8.12-8.04 (m, 1H), 7.98 (s, 1H),7.53-7.42 (m, 1H), 4.78 (dd, J=9.0, 4.4 Hz, 1H), 3.90-3.54 (m, 2H), 2.76(dd, J=16.6, 4.4 Hz, 1H), 2.53 (dd, J=16.6, 9.4 Hz, 1H), 2.41 (s, 3H),1.16 (t, J=7.2 Hz, 3H); ESIMS m/z 421 ([M+H]⁺).

Example 95 Preparation ofN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-3-(((2,2-difluorocyclopropyl)methyl)thio)-N-ethyl-4,4,4-trifluorobutanamide(Molecule 634)

To a solution of methanol (21.1 mg, 0.66 mmol) in THF (1 mL) was addedsodium hydride (26.5 mg, 0.66 mmol, 60% oil suspension). The resultingmixture was stirred for 10 minutes at room temperature andS-(4-((3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)(ethyl)amino)-1,1,1-trifluoro-4-oxobutan-2-yl)ethanethioate (266 mg, 0.63 mmol) in THF (1 mL) was added. Afterstirring for 30 minutes, 2-(bromomethyl)-1,1-difluorocyclopropane (130mg, 0.76 mmol) was added. The mixture was stirred at room temperaturefor an additional 4 hours and diluted with saturated aqueous ammoniumchloride and ethyl acetate. The organic phase was separated and theaqueous phase extracted with ethyl acetate (2×50 mL). The combined ethylacetate extracts were dried over MgSO₄, filtered and concentrated invacuo to give a colorless oil. Purification on silica gel eluting withethyl acetate and hexanes gave the title molecule as a brown oil (89 mg,30% yield): IR (thin film) 3097, 2978, 2937 1664, 1440 cm⁻¹; ¹H NMR (400MHz, CDCl₃) δ 8.96 (d, J=2.7 Hz, 1H), 8.64 (dd, J=4.8, 1.4 Hz, 1H), 8.06(ddd, J=8.4, 2.8, 1.4 Hz, 1H), 7.98 (d, J=2.1 Hz, 1H), 7.47 (dd, J=8.3,4.8 Hz, 1H), 3.94-3.84 (m, 1H), 3.75 (s, 2H), 2.97 (dd, J=13.4, 7.5 Hz,0.55H), 2.85 (s, 1H), 2.79-2.65 (m, 0.45H), 2.60 (m, 1H), 2.43 (dt,J=16.3, 10.0 Hz, 1H), 1.89 (tt, J=12.2, 7.5 Hz, 1H), 1.63-1.49 (m, 1H),1.23-1.13 (m, 4H); ESIMS m/z 469 ([M+H]⁺).

Example 96 Preparation ofN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-2-((cyclopropylmethyl)thio)-N-ethylpropanamide(Molecule 621)

To a solution of methanol (9.99 mg, 0.312 mmol) in THF (1 mL) was addedsodium hydride (12.4 mg, 0.31 mmol, 60% oil suspension). The mixture wasstirred at room temperature for 10 minutes and addedS-(1-((3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)(ethyl)amino)-1-oxopropan-2-yl)ethanethioate (100 mg, 0.28 mmol). After stirring the mixture for 30min, (bromomethyl)cyclopropane (38 mg, 0.28 mmol) was added and themixture stirred for additional 14 hours. The mixture was diluted withsaturated aqueous ammonium chloride (5 mL) and ethyl acetate (15 mL),and the organic phase was separated. The aqueous phase was extractedwith ethyl acetate (5 mL) and the combined organic phase was washed withbrine, dried over MgSO₄ and concentrated in vacuo to give an oilyresidue. This residue was purified on silica gel eluting with mixturesof ethyl acetate and hexanes to give the title molecule as a colorlessgum (31 mg, 30%): IR (thin film) 3081, 2972, 2930, 2871, 1655, 1438cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 8.96 (d, J=2.8 Hz, 1H), 8.63 (dd, J=4.8,1.4 Hz, 1H), 8.13 (s, 1H), 8.04 (ddt, J=8.3, 3.2, 1.6 Hz, 1H), 7.50-7.40(m, 1H), 3.81 (bs, 1H), 3.59 (bs, 1H), 3.33 (d, J=7.4 Hz, 1H), 2.58-2.41(m, 2H), 1.47 (d, J=6.9 Hz, 3H), 1.17 (td, J=7.1, 1.8 Hz, 3H), 0.84 (dt,J=10.3, 7.4, 3.7 Hz, 1H), 0.56-0.38 (m, 2H), 0.25-0.07 (m, 2H); ESIMSm/z 365 ([M+H]⁺).

Molecule 651 in Table 1 was made in accordance with the proceduresdisclosed in Example 96.

Example 97 Preparation ofN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-3-((cyclopropylmethyl)thio)-N-ethylpropanamide(Molecule 619)

To a solution of methanol (9.99 mg, 0.31 mmol) in DMSO (1 mL) was addedsodium hydride (12.4 mg, 0.31 mmol). The mixture was stirred at roomtemperature for 10 minutes and added a solution ofS-(3-((3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)(ethyl)amino)-3-oxopropyl)ethanethioate (100 mg, 0.28 mmol). After stirring the mixture for 30min, (bromomethyl)cyclopropane (38 mg, 0.28 mmol) was added and themixture stirred for an additional 30 minutes. The mixture was dilutedwith saturated aqueous NH₄Cl and ethyl acetate and the organic phaseseparated. The aqueous phase was extracted with ethyl acetate and thecombined organic phase was washed with brine, dried over MgSO₄ andconcentrated in vacuo to give a light brown oil. This oil was purifiedon silica gel eluting with mixtures of hexanes and ethyl acetate to givethe title molecule as a colorless gum (33 mg, 31%): IR (thin film) 3080,2978, 2930, 1660, 1584 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 8.95 (d, J=2.8Hz, 1H), 8.63 (dd, J=4.7, 1.5 Hz, 1H), 8.12-8.01 (m, 1H), 7.98-7.92 (m,1H), 7.53-7.40 (m, 1H), 3.78-3.62 (m, 2H), 2.95-2.84 (m, 2H), 2.51-2.38(m, 4H), 1.20-1.11 (m, 3H), 0.94 (s, 1H), 0.60-0.34 (m, 2H), 0.24-0.09(m, 2H); ESIMS m/z 365 ([M+H]⁺).

Example 98 Preparation ofN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-2-((cyclopropylmethyl)thio)-N-ethylacetamide(Molecule 620)

To a solution of methanol (10.4 mg, 0.32 mmol) in DMSO (1 mL) was addedsodium hydride (13 mg, 0.32 mmol). The mixture was stirred at roomtemperature for 10 minutes and cooled to 0-5° C. and added a solution ofS-(2-((3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)(ethyl)amino)-2-oxoethyl)ethanethioate (100 mg, 0.29 mmol). After stirring the mixture for 30min, (bromomethyl)cyclopropane (39 mg, 0.29 mmol) was added and themixture stirred for additional 2 hours. The mixture was diluted withsaturated aqueous ammonium chloride (5 mL) and ethyl acetate (15 mL),and the organic phase was separated. The aqueous phase was extractedwith ethyl acetate (5 mL) and the combined organic phase was washed withbrine, dried over MgSO₄ and concentrated in vacuo to give an oilyresidue. This residue was purified on silica gel eluting with ethylacetate and hexanes to give the title molecule as a colorless gum (38mg, 37%): IR (thin film) 3080, 2975, 2931, 1657, 1584 cm⁻¹; ¹H NMR (400MHz, CDCl₃) δ 8.96 (dd, J=2.7, 0.7 Hz, 1H), 8.63 (dd, J=4.8, 1.4 Hz,1H), 8.08 (s, 1H), 8.04 (ddd, J=8.4, 2.8, 1.5 Hz, 1H), 7.46 (ddd, J=8.4,4.7, 0.8 Hz, 1H), 3.6 (bs, 1H), 3.17 (s, 1H), 2.61 (d, J=7.1 Hz, 2H),1.17 (t, J=7.2 Hz, 2H), 1.05-0.91 (m, 1H), 0.55 (dd, J=7.9, 1.5 Hz, 2H),1.21-1.10 (m, 3H), 0.24 (dd, J=4.8, 1.4 Hz, 2H); ESIMS m/z 351 ([M+H]⁺).

Molecule 650 in Table 1 was made in accordance with the proceduresdisclosed in Example 98.

Example 99 Preparation ofN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-3-((3,3-dichloroallyl)thio)-N-methylpropanamide(Molecule 649)

To a solution ofN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-3-mercapto-N-methylpropanamide(100 mg, 0.34 mmol) in DMSO (1 mL) was added sodium hydride (14.8 mg,0.37 mmol). The mixture was stirred at room temperature for 10 min andcooled to 0-5° C. 1,1,3-Trichloroprop-1-ene (49.0 mg, 0.34 mmol) wasadded, and the mixture stirred for an additional 45 minutes. The mixturewas diluted with saturated aqueous NH₄Cl and ethyl acetate and theorganic phase was separated. The aqueous phase was extracted with ethylacetate and the combined organic phase was washed with brine, dried overMgSO₄ and concentrated in vacuo to give a light brown oil. This oil waspurified on silica gel eluting with mixtures of hexanes to give thetitle molecule as a colorless gum (60 mg, 43.9%): IR (thin film) 3078,2926, 1659, 1583, 1458, 1437, 803 cm⁻¹; H NMR (400 MHz, CDCl₃) δ 8.94(dd, J=2.7, 0.7 Hz, 1H), 8.63 (dd, J=4.8, 1.5 Hz, 1H), 8.04 (ddd, J=8.3,2.7, 1.4 Hz, 1H), 7.98 (s, 1H), 7.47 (ddd, J=8.3, 4.7, 0.7 Hz, 1H), 5.30(s, 1H), 3.51 (s, 2H), 3.25 (s, 3H), 2.87 (t, J=7.3 Hz, 2H), 2.52 (t,J=7.3 Hz, 2H); ESIMS m/z 406 ([M+2]⁺), 403.7 ([M−1]⁻).

Example 100 Preparation of2-chloro-N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethylpropanamide

To a solution of 3-chloro-N-ethyl-1-(pyridin-3-yl)-1H-pyrazol-4-amine(1.0 g, 4.49 mmol) in 1,2-dichloroethane (44.9 ml) at 0° C. were addeddiisopropylethylamine (0.941 ml, 5.39 mmol) and 2-chloropropanoylchloride (0.436 ml, 4.49 mmol), sequentially. The reaction was allowedto warm to ambient temperature and was stirred for 1.5 hr. The reactionwas quenched with the addition of aqueous NaHCO₃ and the layers werequickly separated. The aqueous layer was extracted with CH₂Cl₂ (3×50 mL)and the combined organics were dried over Na₂SO₄, filtered andconcentrated in vacuo. The crude residue was purified via flashchromatography (30 to 100% EtOAc/Hex) to give the title molecule as awhite solid (1.301 g, 93%): mp 94-105° C.; ¹H NMR (400 MHz, CDCl₃) δ8.97 (d, J=2.7 Hz, 1H), 8.64 (dd, J=4.8, 1.5 Hz, 1H), 8.09 (s, 1H), 8.04(ddd, J=8.4, 2.7, 1.5 Hz, 1H), 7.47 (dd, J=8.3, 4.8 Hz, 1H), 4.27 (q,J=6.5 Hz, 1H), 3.83 (s, 1H), 3.63 (s, 1H), 1.64 (d, J=6.5 Hz, 3H), 1.19(t, J=7.2 Hz, 3H); ESIMS m/z 313 ([M+H]⁺).

The following molecules were made in accordance with the proceduresdisclosed in Example 100:

2-chloro-N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethylbutanamide

Mp 95-103° C.; ¹H NMR (400 MHz, CDCl₃) δ 8.98 (d, J=2.6 Hz, 1H), 8.64(dd, J=4.8, 1.4 Hz, 1H), 8.08 (s, 1H), 8.05 (ddd, J=8.4, 2.7, 1.4 Hz,1H), 7.47 (dd, J=8.3, 4.7 Hz, 1H), 3.99 (m, 1H), 3.86 (br. s, 1H), 3.60(br. s, 1H), 2.13 (dt, J=14.6, 7.3 Hz, 1H), 1.91 (dt, J=14.5, 7.3 Hz,1H), 1.19 (t, J=7.2 Hz, 3H), 0.97 (t, J=7.3 Hz, 3H); ESIMS m/z 327([M+H]⁺).

2-chloro-N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethylacetamide(Compound Y2007)

Due to observed decomposition when left at ambient temperaturesovernight, the title molecule was immediately used in subsequentreactions: ¹H NMR (400 MHz, CDCl₃) δ 8.96 (d, J=2.6 Hz, 1H), 8.65 (dd,J=4.7, 1.3 Hz, 1H), 8.07-8.01 (m, 2H), 7.47 (dd, J=8.3, 4.7 Hz, 1H),3.93 (s, 2H), 3.79-3.68 (bs, 2H), 1.19 (t, J=7.2 Hz, 3H).

N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-2-((1-chloro-2,2,2-trifluoroethyl)thio)-N-ethylacetamide(Molecule 638)

Supporting analytical data for the title molecule can be found in Table2.

Example 101 Preparation ofS-(1-((3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)(ethyl)amino)-1-oxopropan-2-yl)ethanethioate (Molecule 685)

To a solution of2-chloro-N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethylpropanamide(1.0 g, 3.19 mmol) in acetone (6.39 ml) was added potassiumethanethioate (0.438 g, 3.83 mmol). Reaction vessel was capped andheated to 60° C. for 1.5 h. The reaction was cooled and poured into aseparatory funnel containing water (20 mL) and EtOAc (20 mL). The layerswere separated and aqueous layer was extracted with EtOAc (3×20 mL). Thecombined organic extract was dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The crude residue was purified (flashchromatography, 20 to 100% EtOAc/Hex) to give the title molecule as abrown, highly viscous oil (1.07 g, 90%).

The following molecules were made in accordance with the proceduresdisclosed in Example 101:

S-(1-((3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)(ethyl)amino)-1-oxobutan-2-yl)ethanethioate

Mp 116-122° C.; ¹H NMR (400 MHz, CDCl₃) δ 8.97 (d, J=2.6 Hz, 1H), 8.63(dd, J=4.8, 1.5 Hz, 1H), 8.13-7.99 (m, 2H), 7.46 (dd, J=8.3, 4.7 Hz,1H), 4.14 (t, J=7.3 Hz, 1H), 3.85 (br. s, 1H), 3.57 (br. s, 1H), 2.27(s, 3H), 1.98 (dt, J=14.2, 7.1 Hz, 1H), 1.74-1.62 (m, 1H), 1.16 (t,J=7.2 Hz, 3H), 0.92 (t, J=7.4 Hz, 3H); ESIMS m/z 367 ([M+H]⁺).

S-(2-((3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)(ethyl)amino)-2-oxoethyl)ethanethioate (Molecule 694)

Mp 117-124° C.; ¹H NMR (400 MHz, CDCl₃) δ 8.98 (dd, J=2.7, 0.7 Hz, 1H),8.64 (dd, J=4.8, 1.5 Hz, 1H), 8.09 (s, 1H), 8.06 (ddd, J=8.3, 2.7, 1.5Hz, 1H), 7.47 (ddd, J=8.3, 4.8, 0.7 Hz, 1H), 3.84-3.65 (m, 2H), 3.61 (s,2H), 2.33 (s, 3H), 1.17 (t, J=7.2 Hz, 3H); ESIMS m/z 339 ([M+H]⁺).

Example 102 Preparation ofN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-2-((2,2,2-trifluoroethyl)thio)propanamide(Molecule 635)

To a dry round-bottom flask under N₂ were added sodium hydride (0.018 g,0.446 mmol) and THF (2.1 mL), followed by methanol (0.018 mL, 0.446mmol). The reaction was allowed to stir at ambient temperature untilcessation of hydrogen evolution was observed (˜45 min). The reaction wasthen cooled at 0° C. andS-(1-((3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)(ethyl)amino)-1-oxopropan-2-yl)ethanethioate (0.150 g, 0.425 mmol) in THF (2.1 mL) was added. Thereaction was warmed to ambient temperature and stirred for 30 min. Thereaction was again cooled at 0° C. and 1,1,1-trifluoro-2-iodoethane(0.063 ml, 0.638 mmol) in THF (2.1 mL) was added. The reaction waswarmed to room temperature and stirred overnight. The reaction wasdiluted in EtOAc (20 mL) and quenched with H₂O (5 mL). The layers wereseparated and the aqueous layer was extracted with EtOAc (3×10 mL). Thecombined organic extracts were dried over Na₂SO₄, filtered andconcentrated in vacuo to give a yellow oil. The crude product waspurified via flash chromatography (0 to 75% CH₂Cl₂/EtOAc) to give thetitle molecule as an opaque, viscous oil (43 mg, 25%): IR (thin film)1657 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 8.96 (d, J=2.6 Hz, 1H), 8.64 (dd,J=4.8, 1.4 Hz, 1H), 8.14-7.96 (m, 2H), 7.47 (dd, J=8.3, 4.8 Hz, 1H),3.82 (s, 1H), 3.59 (s, 1H), 3.44 (s, 1H), 3.25 (qd, J=10.2, 3.8 Hz, 2H),1.48 (d, J=6.8 Hz, 3H), 1.17 (t, J=7.2 Hz, 3H); ¹⁹F NMR (376 MHz, CDCl₃)δ-66.16; ESIMS m/z 393 ([M+H]⁺).

Molecules 637, 639-642, and 652 in Table 1 were made in accordance withthe procedures disclosed in Example 102.

Example 103 Preparation ofN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-2-((2-fluorovinyl)thio)propanamide(Molecule 654)

To a dry round-bottom flask under N₂ were added a 60% dispersion of NaHin mineral oil (0.043 g, 1.063 mmol) and THF (2.1 mL), followed bymethanol (0.086 mL, 2.126 mmol). The reaction was allowed to stir atambient temperature until cessation of hydrogen evolution was observed(˜45 min). The reaction was then cooled at 0° C. andS-(1-((3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)(ethyl)amino)-1-oxopropan-2-yl)ethanethioate (0.150 g, 0.425 mmol) in THF (2.1 mL) was added. Reactionwas warmed to room temperature and stirred for 30 min. The reaction wasagain cooled at 0° C. and 2-bromo-1,1-difluoroethane (0.101 mL, 1.275mmol) in THF (2.1 mL) was added. Reaction was warmed to room temperatureand stirred overnight. LC-MS analysis indicated presence of twoproducts, the major corresponding to the desired elimination product andthe minor corresponding to the initial alkylation. Therefore, thereaction was cooled to 0° C. and transferred to a vial containingadditional NaOMe (freshly prepared by mixing NaH (5.86 mg, 0.147 mmol)and MeOH (5.93 μL, 0.147 mmol) in THF (0.73 mL) at 0° C. After stirringan additional 18 h, reaction was diluted in EtOAc (5 mL) and quenchedwith H₂O (5 mL). Aqueous layer was extracted with EtOAc (3×10 mL) andthe combined organic extracts were dried over Na₂SO₄, filtered, andconcentrated in vacuo to give a yellow oil. The crude residue waspurified via flash chromatography (25-80% EtOAc/Hex) to give aninseparable mixture of olefin isomers (˜3:2, E/Z) as an opaque, viscousoil (15 mg, 10%): IR (thin film) 3091, 1656 cm⁻¹; H NMR (400 MHz, CDCl₃)δ 8.97 (m, 1H), 8.64 (dd, J=4.7, 1.4 Hz, 1H), 8.13 (s, 0.4H), 8.04 (m,1.6H), 7.54-7.41 (m, 1H), 6.79 (dd, J=83.3, 11.0 Hz, 0.6H), 6.75 (dd,J=82.7, 4.3 Hz, 0.4H), 5.97 (dd, J=12.7, 11.0 Hz, 0.6H), 5.68 (dd,J=39.8, 4.3 Hz, 0.4H), 3.82 (br. s, 1H), 3.72-3.47 (m, 1H), 3.47-3.20(m, 1H), 1.50 (d, J=6.9 Hz, 1.2H), 1.42 (d, J=6.8 Hz, 1.8H), 1.17 (m,3H); ESIMS m/z 355 ([M+H]⁺).

Example 104 Preparation ofN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-3-((2,2,2-trifluoroethyl)thio)propanamide(Molecule 636)

To a solution of3-chloro-N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethylpropanamide(100 mg, 0.32 mmol) in THF (0.3 mL) was added sodium iodide (4.7 mg,0.032 mmol), 2,2,2-trifluoroethanethiol (148 mg, 1.3 mmol), andN,N-di-iso-propylethylamine (222 μl, 1.277 mmol). The reaction mixturewas heated overnight at 50° C., diluted with DCM and washed with 5% KOHsolution. The phases were separated, concentrated, and purified bysilica gel chromatography eluting with 0-40% acetone in hexanes toafford the title molecule as a colorless oil (109 mg, 83%): ¹H NMR (400MHz, CDCl₃) δ 8.95 (d, J=2.4 Hz, 1H), 8.63 (dd, J=4.7, 1.4 Hz, 1H), 8.05(ddd, J=8.3, 2.7, 1.4 Hz, 1H), 7.96 (d, J=7.1 Hz, 1H), 7.46 (ddd, J=8.3,4.8, 0.6 Hz, 1H), 3.72 (q, J=7.1 Hz, 2H), 3.10 (q, J=10.0 Hz, 2H), 2.96(t, J=7.0 Hz, 2H), 2.47 (t, J=7.0 Hz, 2H), 1.17 (t, J=7.2 Hz, 3H); ¹⁹FNMR (376 MHz, CDCl₃) δ-66.56 (s); ESIMS m/z 393 ([M+H]⁺).

Example 105 Preparation ofN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N,2-dimethyl-3-((trifluoromethyl)thio)propanamide(Molecule 647)

To a solution of 2-methyl-3-((trifluoromethyl)thio)propanoic acid (0.200g, 1.065 mmol) in DCM (1.0 mL) was added oxalyl dichloride (0.093 mL,1.065 mmol) and 1 drop of DMF and stirred at ambient temperature for 1hour (gas evolution was observed). The reaction mixture was concentratedand the crude acid chloride was dissolved in DCM (0.3 mL) which wassubsequently added to a pre-stirred solution of3-chloro-N-methyl-1-(pyridin-3-yl)-1H-pyrazol-4-amine dihydrochloride(0.100 g, 0.355 mmol) and N,N-dimethylpyridin-4-amine (0.130 g, 1.065mmol) in DCM (1.0 mL) and stirred overnight at room temperature. Thereaction mixture was diluted with saturated NaHCO₃ and extracted withDCM. The organic layer was dried over Na₂SO₄, filtered and concentrated.The crude material was purified via flash chromatography eluting with0-100% EtOAc/hexanes to give the title molecule as a yellow oil (93 mg,65.7%): IR (thin film) 1654 cm⁻¹; H NMR (400 MHz, CDCl₃) δ 8.96 (d,J=2.6 Hz, 1H), 8.64 (dd, J=4.7, 1.3 Hz, 1H), 8.08-8.00 (m, 1H), 7.98 (d,J=8.3 Hz, 1H), 7.51-7.44 (m, 1H), 4.07-3.36 (m, 2H), 3.25-3.11 (m, 1H),2.94-2.77 (m, 2H), 1.22-1.15 (m, 6H); ESIMS m/z 394 ([M+H])⁺).

Molecule 648 in Table 1 was made in accordance with the proceduresdisclosed in Example 105

Example 106 Preparation ofN-methyl-N-(1-methyl-3-(pyridin-3-yl)-1H-pyrazol-5-yl)-3-((3,3,3-trifluoropropyl)thio)propanamide(Compound 1011)

A solution of 3-((3,3,3-trifluoropropyl)thio)propanoic acid (75 mg,0.372 mmol), DMAP (110 mg, 0.903 mmol), and N,1-dimethyl-3-(pyridin-3-yl)-1H-pyrazol-5-amine (50 mg, 0.266 mmol) indry diethyl ether (886 μL) was cooled to 0° C. under N₂.N,N′-Dicyclohexylcarbodiimide (DCC) (132 mg, 0.638 mmol) was added andthe reaction was warmed up to room temperature under N₂, then stirred atroom temperature overnight. The reaction mixture was filtered usingadditional diethyl ether (0.5 mL) to remove salts and concentrated underreduced pressure. Purification by silica gel chromatography by elutingwith 0-90% hexanes/EtOAc afforded the title compound as a clear oil (64mg, 61%).

Example 107 Preparation oftert-butyl(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)(2-hydroxyethyl)carbamate(Compound Y2151)

To a solution of2-((tert-butoxycarbonyl)(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)amino)ethylacetate (841 mg, 2.21 mmol) in MeOH (7.3 mL) was added potassiumcarbonate (305 mg, 2.21 mmol). The reaction was stirred at roomtemperature overnight. The reaction mixture was diluted with water (10mL) and extracted with EtOAc (2×10 mL). The organic layer was washedwith saturated aqueous NaHCO₃ (10 mL), dried over MgSO₄ andconcentrated. Et₂O was added and the resulting precipitate was collectedby filtration to afford the title compound as a white solid (249 mg,32%).

Example 108 Preparation of2-((tert-butoxycarbonyl)(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)amino)ethylmethanesulfonate

To a solution oftert-butyl(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)(2-hydroxyethyl)carbamate(574 mg, 1.69 mmol) in dry CH₂Cl₂ (4.0 mL), triethylamine (260 μl, 1.86mmol) was added under N₂. Methanesulfonyl chloride (145 μl, 1.864 mmol)was added dropwise and the reaction was stirred at room temperature for4 h. After the reaction was deemed complete by LCMS, the reactionmixture was diluted with CH₂Cl₂ (10 mL) and washed with water (2×10 mL)and brine (10 mL). The organic layer was dried and concentrated underreduced pressure. Purification by silica gel chromatography by elutingwith 10-100% hexanes/EtOAc afforded the title compound as a colorlessliquid (330 mg, 44%): ¹H NMR (400 MHz, CDCl₃) δ 9.00 (s, 1H), 8.59 (dd,J=4.9, 1.5 Hz, 1H), 8.12 (s, 1H), 8.06 (ddd, J=8.4, 2.8, 1.3 Hz, 1H),7.46 (dd, J=8.4, 4.7 Hz, 1H), 4.52-4.31 (m, 2H), 3.89 (t, J=5.1 Hz, 2H),3.04 (s, 3H), 2.19 (s, 3H), 1.68-1.32 (m, 6H); ESIMS m/z 417 ([M+H]⁺).

Example 109 Preparation oftert-butyl(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)(2-(pyrrolidin-1-yl)ethyl)carbamate(Compound Y2152)

To a solution of2-((tert-butoxycarbonyl)(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)amino)ethylmethanesulfonate (129 mg, 0.309 mmol) in dry DMF (884 al), triethylamine(51.8 μl, 0.371 mmol) and pyrrolidine (37.5 al, 0.449 mmol) was addedunder N₂. The reaction was then heated at 80° C. under N₂ overnight.After the reaction was deemed complete by LCMS, the reaction mixture wasdiluted with water (10 mL) and saturated aqueous NaHCO₃ (5 mL), thenextracted with EtOAc (3×10 mL). The organic layer was dried over MgSO₄and concentrated under reduced pressure. Purification by silica gelchromatography by eluting with 0-50% CH₂Cl₂/MeOH afforded the titlecompound as an off-white solid (65 mg, 51%).

Example 110 Preparation ofN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-(oxiran-2-ylmethyl)-3-((3,3,3-trifluoropropyl)thio)propanamide(Compound 928)

A solution ofN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-3-((3,3,3-trifluoropropyl)thio)propanamide(109 mg, 0.288 mmol) in dry DMF (882 μl) was cooled to 0° C. in an icebath under N₂. Sodium hydride (16.11 mg, 0.403 mmol, 60% dispersion inmineral oil) was carefully added and the reaction was stirred at 0° C.for 30 min. 2-(Bromomethyl)oxirane (47.6 μl, 0.576 mmol) was then addedand stirred for 30 min at 0° C. The reaction was slowly warmed up toroom temperature and stirred overnight under N₂. The reaction mixturewas quenched with water (15 mL) and extracted with EtOAc (3×10 mL). Theorganic layer was dried over MgSO₄ and concentrated under reducedpressure. Purification by silica gel chromatography by eluting with0-90% hexane/EtOAc afforded the title compound as an yellow oil (28 mg,21%).

Example 111 Preparation ofN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-(ethylcarbamoyl)-3-((3,3,3-trifluoropropyl)thio)propanamide(Compound 988)

To a solution ofN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-3-((3,3,3-trifluoropropyl)thio)propanamide(106 mg, 0.280 mmol) in dry CH₂Cl₂ (1.8 mL), isocyanatoethane (44.3 μl,0.560 mmol) was added. The reaction mixture was stirred at roomtemperature overnight then refluxed for 2 h. The solvent was switched toTHF and another portion of isocyanatoethane (44.3 μl, 0.560 mmol) wasadded and refluxed for additional 2 h. Toluene (1.9 mL) was added alongwith another portion of isocyanatoethane (44.3 μl, 0.560 mmol) and thereaction was refluxed overnight. A small amount of product formation wasobserved by LCMS. The reaction mixture was poured into a 5 mL microwavevial with additional toluene (0.5 mL) and acetonitrile (0.5 mL) alongwith another portion of isocyanatoethane (44.3 μl, 0.560 mmol). Thereaction was capped and placed on a Biotage® Initiator microwave reactorfor total of 9 h at 120° C., then for 8 h at 125° C., with externalIR-sensor temperature monitoring from the side of the vessel. Thereaction mixture was concentrated under reduced pressure. Purificationby silica gel chromatography by eluting with 0-10% CH₂Cl₂/MeOH and asubsequent purification eluting with 0-100% water/acetonitrile affordedthe title compound as a white solid (36 mg, 27%). Reference: J. Org.Chem., 1951, 16, 1879-1890.

Example 112 Preparation of4-((3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)(ethyl)amino)-4-oxobutanoicacid (Compound Y2187)

In a 100 mL round bottom flask (RBF),3-chloro-N-ethyl-1-(pyridin-3-yl)-1H-pyrazol-4-amine (500 mg, 2.25mmol), DMAP (27.4 mg, 0.225 mmol), triethylamine (0.469 mL, 3.37 mmol),and dihydrofuran-2,5-dione (449 mg, 4.49 mmol) was added withdichloroethane (22.5 mL). The reaction was heated at 60° C. under N₂overnight. The reaction mixture was concentrated and purified by silicagel chromatography by eluting with 0-15% CH₂Cl₂/MeOH to afford the titlecompound as an off-white solid (635 mg, 86%).

Example 113 Preparation of S-(3,3,3-trifluoropropyl)4-((3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)(ethyl)amino)-4-oxobutanethioate(Compound 979)

A solution of4-((3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)(ethyl)amino)-4-oxobutanoicacid (100 mg, 0.310 mmol), 3,3,3-trifluoropropane-1-thiol (42.0 μl,0.387 mmol), and DMAP (3.79 mg, 0.031 mmol) in dry CH₂Cl₂ (620 μl) wascooled to 0° C. DCC (63.9 mg, 0.310 mmol) was added and the reaction waswarmed up to room temperature under N₂, then stirred overnight. Thereaction mixture was filtered using additional CH₂Cl₂ (1 mL) to removesalts and concentrated under reduced pressure. Purification by silicagel flash column chromatography eluting with 10-90% hexanes/EtOAcafforded the title compound as a slightly yellow clear viscoussemi-solid (83 mg, 60%). Reference: J. Am. Chem. Soc., 2009, 131,14604-14605.

Example 114 Preparation of 3,3,3-trifluoropropyl4-((3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)(ethyl)amino)-4-oxobutanoate(Compound Y2154)

A solution of4-((3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)(ethyl)amino)-4-oxobutanoicacid (101 mg, 0.313 mmol), sodium bicarbonate (526 mg, 6.26 mmol), and3-bromo-1,1,1-trifluoropropane (66.6 μl, 0.626 mmol) in DMF (1565 μl)was stirred at room temperature under N₂ overnight. The reaction wasquenched with water (15 mL) and extracted with CH₂Cl₂ (3×10 mL). Theorganic layer was dried and concentrated under reduced pressure.Purification by silica gel chromatography by eluting with 0-100%hexanes/EtOAc afforded the title compound as a clear oil (36 mg, 26%).Reference: Syn. Commun., 2008, 38, 54-71.

Example 115 Preparation of2-((2,2,2-trifluoroethyl)thio)ethyl(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)(ethyl)carbamate(Compound 970)

A solution of 3-chloro-N-ethyl-1-(pyridin-3-yl)-1H-pyrazol-4-amine (170mg, 0.763 mmol) in dichloroethane (2 mL) was cooled to 0° C. Under N₂,phosgene (708 μl, 0.992 mmol, 15 wt % in toluene) was added and after 5minutes N,N-dimethylpyridin-4-amine (196 mg, 1.603 mmol) was added inone portion. The ice bath was removed and the mixture was stirred atroom temperature for 5 minutes and at 80° C. for 50 min. The mixture wascooled to room temperature and then2-((2,2,2-trifluoroethyl)thio)ethanol (251 mg, 1.57 mmol) was added withCH₂Cl₂ (0.5 mL) followed by another portion ofN,N-dimethylpyridin-4-amine (196 mg, 1.60 mmol). The reaction mixturewas heated under N₂ at 80° C. for 2 h. The reaction mixture was dilutedwith CH₂Cl₂ (10 mL) and saturated aqueous NH₄Cl (10 mL). The organiclayer was separated, dried, and concentrated. Purification by silica gelchromatography by eluting with 0-100% hexanes/EtOAc and a subsequentpurification eluting with 0-100% water/acetonitrile afforded the titlecompound as a cloudy white oil (33 mg, 10%).

Example 116 Preparation of1-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-1-ethyl-3-(((3,3,3-trifluoropropyl)thio)methyl)urea(Compound 990)

To a solution of 2-((3,3,3-trifluoropropyl)thio)acetic acid (696 mg,3.70 mmol) in CH₂Cl₂ (7.40 mL), oxalyl chloride (1.619 mL, 18.49 mmol)was added along with a drop of DMF at room temperature. Once DMF wasadded, gas evolution was observed and continued for about 30 min. Thereaction mixture was stirred at room temperature for total of 1 h thenthe solvent was removed under reduced pressure. Acetone (18.50 mL) wasadded to the concentrated material and the reaction was cooled to 0° C.in an ice bath. To that, a solution of sodium azide (265 mg, 4.07 mmol)in water (1 mL) was added dropwise. The reaction was stirred at 0° C.for 1 h. The reaction mixture was diluted with water (15 mL) and stirredat room temperature for 5 min. Dichloromethane (10 mL) was added and theorganic layer was separated, dried, and concentrated under reducedpressure to afford 2-((3,3,3-trifluoropropyl)thio)acetyl azide as darkbrown-green oil. Dry CH₂Cl₂ (4193 μl) was added to the crude azide andrefluxed for 2 h. The reaction was cooled to room temperature and3-chloro-N-ethyl-1-(pyridin-3-yl)-1H-pyrazol-4-amine (140 mg, 0.629mmol) was added. The reaction was stirred overnight at room temperature.The reaction was concentrate under reduced pressure and purified bysilica gel chromatography by eluting with 0-10% CH₂Cl₂/MeOH to affordtitle compound as a light brown solid (179 mg, 68%). Reference: J. Org.Chem., 2003, 68, 9453-9455.

Example 117 Preparation of3-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-5-(hydroxymethyl)oxazolidin-2-one(Compound Y2148)

To a solution oftert-butyl(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)(oxiran-2-ylmethyl)carbamate(321 mg, 0.915 mmol) in dry CH₂Cl₂ (915 μL), trifluoroacetic acid (915μL) was added under N₂. The reaction mixture was stirred at roomtemperature for 90 min under N₂. The reaction mixture was diluted withtoluene (10 mL) and concentrated under reduced pressure to almostdryness. EtOAc (5 mL) was added and the reaction was quenched withsaturated aqueous NaHCO₃ (10 mL). The organic layer was separated andthe aqueous layer was further extracted with EtOAc (3×5 mL), dried overMgSO₄, and concentrated under reduced pressure to afford the titlecompound as a white foam (134 mg, 47%).

Example 118 Preparation ofN-((3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)(ethyl)carbamoyl)-4-methoxybenzamide(Compound Y2189)

A solution of 4-methoxybenzamide (61.1 mg, 0.404 mmol) and oxalylchloride (44.2 μl, 0.505 mmol) in DCE (1684 μl) was refluxed for 15 hunder N₂. The reaction was cooled to room temperature and3-chloro-N-ethyl-1-(pyridin-3-yl)-1H-pyrazol-4-amine (75 mg, 0.337 mmol)was added and stirred overnight at room temperature. The reactionmixture was diluted with saturated aqueous NaHCO₃ (5 mL) and CH₂Cl₂ (3mL). The phases were separated and the aqueous layer was washed withCH₂Cl₂ (2×3 mL). The combined organic layer was dried and concentrated.Purification by silica gel chromatography eluting with 15-100%hexanes/EtOAc afforded the title compound as white solid (107 mg, 78%).Reference: J. Org. Chem., 1963, 73, 1805.

Example 119 Preparation of1-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-1-ethylurea (CompoundY2186)

A solution ofN-((3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)(ethyl)carbamoyl)benzamide(300 mg, 0.811 mmol) in dry MeOH (2028 μl) and 2 N aqueous NaOH (811 μl,1.62 mmol) was heated at 65° C. for 3 h. The reaction mixture was cooledto room temperature and neutralized with 2 N aqueous HCl andconcentrated under reduced pressure which produced yellow precipitate.The precipitate was collected by filtration, washed with hexanes (3 mL),and dried under vacuum to afford the title compound (109 mg, 48%).

Example 120 Preparation ofN-ethyl-N-(3-methyl-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-4-oxobutanamide(Compound Y2185)

A solution ofN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-4-hydroxybutanamide(41 mg, 0.133 mmol) in dry CH₂Cl₂ (1328 μl) was cooled to 0° C. in anice bath under N₂. Sodium bicarbonate (112 mg, 1.328 mmol) andDess-Martin periodinane (64.8 mg, 0.153 mmol) was added and the reactionwas warmed up to room temperature and stirred for 5 h. LCMS indicated noproduct formation so another portion of Dess-Martin periodinane (64.8mg, 0.153 mmol) was added and stirred at room temperature overnight. Thereaction mixture was diluted with saturated aqueous NaHCO₃ (5 mL) andextracted with CH₂Cl₂ (3×5 mL). The organic layer was dried,concentrated, and purified by silica gel chromatography eluting with0-50% CH₂Cl₂/MeOH to afford the title compound as clear oil (21 mg,46%).

Example 121 Preparation of 1,1,1-trifluoro-7,7-dimethoxyheptan-4-ol

In an oven dried vial with a stir bar, magnesium (77 mg, 3.17 mmol) wasadded and the head space was purged with N₂. Dry THF (4957 μL) was addedwith a crystal of I₂ and heated with a heat gun until bubbles from Mgevolved. Slowly 3-bromo-1,1-dimethoxypropane (395 μL, 2.97 mmol) wasadded and heating continued with a heat gun until Mg was bubbling andthe iodine color disappeared. The reaction mixture was refluxed for 1 hunder N₂ to give a cloudy colorless solution. In a separate oven driedround bottom flask, 4,4,4-trifluorobutanal (208 μL, 1.983 mmol) wasadded with dry THF (10 mL, 0.2M) and cooled to 0 OC. Room temperatureGrignard reagent was added drop wise over 8 min and stirred at 0° C. for30 min. The reaction was warmed up to room temperature and stirred for1.5 h. The reaction was quenched with saturated aqueous NH₄Cl (15 mL)and extracted with CH₂Cl₂ (3×15 mL). The organic layer was dried,concentrated, and purified by silica gel chromatography eluting with0-10% CH₂Cl₂/MeOH to afford the title product as 85% pure clearsemi-solid (372 mg, 69%): IR (thin film) 3442 cm⁻¹; H NMR (400 MHz,CDCl₃) δ 4.39 (t, J=5.2 Hz, 1H), 3.65 (tq, J=8.2, 3.9 Hz, 1H), 3.35 (d,J=0.7 Hz, 6H), 2.40 (dd, J=4.6, 0.7 Hz, 1H), 2.39-2.24 (m, 1H),2.24-2.06 (m, 1H), 1.80-1.72 (m, 2H), 1.72-1.59 (multiple peaks, 3H),1.52 (ddt, J=15.7, 14.2, 7.0 Hz, 1H); ¹⁹F NMR (376 MHz, CDCl₃) δ-66.37;HRMS-FAB (m/z) [M+Na]⁺ calcd for C₉H₁₇F₃NaO₃, 253.1022. found, 253.1025.

Example 122 Preparation of 7,7,7-trifluoro-4-oxoheptanoic acid

To a solution of 1,1,1-trifluoro-7,7-dimethoxyheptan-4-ol (372 mg, 1.616mmol) in dry THF (10.8 mL), 1 N aqueous HCl (8079 μL, 8.08 mmol) wasadded at room temperature. The reaction mixture was stirred for 1 h thendiluted with water (10 mL) and Et₂O (10 mL). The organic layer wasseparated and the aqueous layer was washed with Et₂O (2×10 mL). Thecombined organic layer was washed with saturated aqueous NaHCO₃ (10 mL),dried over MgSO₄, and concentrated. The concentrated crude material wasdissolved in acetone (5 mL) and glacial acetic acid (0.5 mL). Then KMnO₄(766 mg, 4.85 mmol) dissolved in water (10 mL) was added to the stirringsolution drop wise and stirred at room temperature for 2.5 h. GCMSanalysis showed incomplete conversion so more KMnO₄ (510 mg) was addedand the reaction was left stirring overnight at room temperature. Thereaction was diluted with AcOH (15 mL; 2 mL glacial AcOH in 13 mL water)and CH₂Cl₂ (10 mL). The organic layer was separated and the aqueouslayer was extracted with CH₂Cl₂ (2×10 mL). The combined organic layerwas washed with water (15 mL), dried, and concentrated. Purification bysilica gel chromatography eluting with 0-10% CH₂Cl₂/MeOH afforded thetitle compound as white solid (66 mg, 15%): IR (thin film) 1715 cm⁻¹; HNMR (400 MHz, CDCl₃) δ 2.81-2.72 (multiple peaks, 4H), 2.69 (ddd, J=6.8,5.5, 1.2 Hz, 2H), 2.50-2.35 (m, 2H), 1.59 (br s, 1H); ¹⁹F NMR (376 MHz,CDCl₃) δ-66.66.

Example 123 Preparation ofN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-7,7,7-trifluoro-4-oxoheptanamide(Compound Y2188)

A solution of 3-chloro-N-ethyl-1-(pyridin-3-yl)-1H-pyrazol-4-amine (62mg, 0.278 mmol), 7,7,7-trifluoro-4-oxoheptanoic acid (66.2 mg, 0.334mmol), and DMAP (51.0 mg, 0.418 mmol) in dry Et₂O (928 μL) was cooled to0° C. in an ice bath under N₂. DCC (138 mg, 0.668 mmol) was added andthe reaction was warmed up to room temperature slowly. The reaction wasstirred under N₂ overnight at room temperature. A white precipitate wasfiltered off with Et₂O (1 mL) and the filtrate was concentrated.Purification by silica gel chromatography eluting with 0-75%hexanes/EtOAc afforded the title product as brown viscous oil (59 mg,50%).

Example 124 Preparation ofN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-2-hydroxypropanamide

To a solution of1-((3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)(ethyl)amino)-1-oxopropan-2-ylacetate (2.4 g, 7.1 mmol) in methanol (8.9 mL) and tetrahydrofuran (8.9mL) was added 2M lithium hydroxide (7.1 mL, 14.2 mmol). The reactionmixture was stirred for 2 hours at 25° C. The reaction mixture pH wasthen made neutral by the addition of a 2M HCl. The mixture was extractedwith ethyl acetate, and the organic portions were combined, dried overMgSO₄, filtered and concentrated in vacuo to afford the title compoundas a white solid (1.85 g, 88%): mp 137-138° C.; ¹H NMR (400 MHz, DMSO) δ9.08 (d, J=2.5 Hz, 1H), 8.98 (s, 1H), 8.58 (dd, J=4.7, 1.1 Hz, 1H), 8.23(ddd, J=8.4, 2.6, 1.3 Hz, 1H), 7.59 (dd, J=8.3, 4.7 Hz, 1H), 4.97 (d,J=7.6 Hz, 1H), 4.08 (m, 1H), 3.57 (d, J=50.6 Hz, 2H), 1.10 (d, J=6.5 Hz,3H), 1.07 (t, J=7.1 Hz, 3H); ESIMS m/z 295.6 ([M+H]⁺).

Example 1251-((3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)(ethyl)amino)-1-oxopropan-2-ylmethanesulfonate (Compound Y2008)

To a solution ofN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-2-hydroxypropanamide(100 mg, 0.34 mmol) in tetrahydrofuran (1.1 mL) was added sodium hydride(14.9 mg, 0.34 mmol). The mixture was stirred for 15 min and thenmethanesulfonyl chloride (58.3 mg, 0.51 mmol) was added. The reactionmixture was stirred for 16 hours, diluted with CH₂Cl₂, and washed withwater. The phases were separated, dried, concentrated in vacuo andpurified by silica gel chromatography eluting with 0-70% acetone inhexanes to afford the title compound as a light yellow oil (88 mg, 70%):IR (thin film) 2980, 2936, 1676 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 9.00 (d,J=2.5 Hz, 1H), 8.64 (dd, J=4.8, 1.4 Hz, 1H), 8.12 (s, 1H), 8.02 (ddd,J=8.3, 2.7, 1.4 Hz, 1H), 7.46 (ddd, J=8.3, 4.8, 0.6 Hz, 1H), 5.17 (q,J=6.7 Hz, 1H), 3.71 (m, 2H), 3.13 (s, 3H), 1.50 (d, J=6.7 Hz, 3H), 1.19(t, J=7.2 Hz, 3H); ESIMS m/z 373.6 ([M+H]⁺).

Example 126 Preparation ofN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-3-((3,3-difluorocyclobutyl)thio)-N-ethylpropanamide(Compound 910)

N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-3-((3-oxocyclobutyl)thio)propanamide(100 mg, 0.264 mmol) was dissolved in CH₂Cl₂ (2 mL) and stirred at 0° C.Deoxofluor® (0.083 mL, 0.449 mmol) and EtOH (2.312 μl, 0.040 mmol) wasadded to the solution at 0° C. The resulting solution was warmed to 25°C. slowly and stirred at 25° C. After 4 hours, 1 more equivalent ofDeoxofluor® (50 μL) and another 2.5 μL of EtOH was added. The reactionwas worked up by slow addition of NaHCO₃ solution and stirred for 30 minat 25° C. The mixture was diluted with water (20 mL) and extracted withCH₂Cl₂ (3×20 mL). The combined organic layer was washed with 0.01 M HCl,dried over Na₂SO₄ and purified with silica gel chromatography (0-100%EtOAc/hexane) to give the title compound as a light yellow oil (19 mg,18%).

Example 127 Preparation ofN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-3-(vinylsulfinyl)propanamide(Compound 1004)

To a 7 mL vial was addedN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-3-mercaptopropanamide(0.050 g, 0.161 mmol), 1,2-dibromoethane (0.907 g, 4.83 mmol) followedby 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (0.024 g, 0.161 mmol). Thesolution was stirred at 25° C. overnight, then it was concentrated andre-dissolved in hexafluoroisopropanol (1 mL). Hydrogen peroxide (0.055g, 0.483 mmol) was added and the solution was stirred at 25° C. for 2hours, then worked up with sodium sulfite solution and extracted withCH₂Cl₂. The crude reaction mixture was purified by silica gelchromatography (0-10% MeOH/CH₂Cl₂) to give the title compound as a brownoil (33 mg, 58%).

Example 128 Preparation of3-(N-carbamoyl-S-methylsulfonimidoyl)-N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethylpropanamide(Compound Y2099)

N-[3-chloro-1-(3-pyridyl)pyrazol-4-yl]-3-(N-cyano-S-methyl-sulfonimidoyl)-N-ethyl-propanamide(320 mg, 0.840 mmol) was dissolved in cone. sulfuric acid (4 mL, 75mmol) and stirred at 25° C. for 16 h. The solution was poured into aflask with ice and solid NaHCO₃ was added slowly until the aqueous layerwas neutral. The aqueous layer was extracted with CH₂Cl₂ and thecombined organic layers were dried over Na₂SO₄ and concentrated. Thecrude reaction mixture was purified by silica gel chromatography (0-10%MeOH/CH₂Cl₂) to give the title compound as white solid (135 mg, 40%).

Example 129 Preparation of4-chloro-N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)butanamide(Compound Y2166)

To a solution of 3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-amine (1.34 g,6.89 mmol) in CH₂Cl₂ (11 mL) cooled to 0° C. was added triethylamine(1.439 mL, 10.33 mmol) and 4-chlorobutanoyl chloride (0.971 g, 6.89mmol). The solution was allowed to slowly warm to 25° C. and stirred for1 h. The reaction was diluted with water (20 mL) and extracted withCH₂Cl₂ (3×20 mL). The combined organic layers were dried, concentratedand purified with chromatography (0-100% EtOAc/hexane) to give the titlecompound as white solid (1.87 g, 91%).

Example 130 Preparation of1-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)pyrrolidin-2-one (CompoundY2167)

A solution of4-chloro-N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)butanamide (1.82g, 6.08 mmol) in THF (50 mL) was cooled to 0° C. NaH (0.280 g, 7.00mmol) was added and the mixture was slowly warmed to 25° C. and stirredfor 2 h. The mixture was diluted with water and extracted with CH₂Cl₂(3×20 mL). The combined organic layers were dried, concentrated andpurified with silica gel chromatography (0-10% MeOH/CH₂Cl₂) to give thetitle compound as yellow solid (1.70 g, 96%).

Example 131 Preparation of1-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-3-methylenepyrrolidin-2-one(Compound Y2168)

A solution of1-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)pyrrolidin-2-one (1600 mg,6.09 mmol) in CH₂Cl₂ (15 mL) was cooled to 0° C. Triethylamine (1.273mL, 9.14 mmol) and trimethylsilyl trifluoromethanesulfonate (1.431 mL,7.92 mmol) were added, and the resulting deep red solution was stirredat 0° C. for 45 min. Eschenmoser's salt (dimethylmethylideneammoniumiodide)(1465 mg, 7.92 mmol) was then added and the solution was allowedto warm to 25° C. and stir overnight. The solution was diluted withCH₂Cl₂ (30 mL) and 1N HCl (30 mL) was added and the mixture was stirredfor 10 min before it was neutralized with NaOH solution to pH=12. Themixture was extracted with CH₂Cl₂, and the combined organic layers weredried, concentrated and purified with silica gel chromatography (0-10%MeOH/CH₂Cl₂) to give the title compound as light yellow solid (866 mg,52%).

Example 132 Preparation of1-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-3-((methylthio)methyl)pyrrolidin-2-one(Compound 955)

1-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-3-methylenepyrrolidin-2-one(400 mg, 1.46 mmol) was dissolved in THF (6 mL). Potassium hydroxide(384 mg, 5.82 mmol) dissolved in water (1 mL) was added to the mixture,followed by S,S-dimethyl carbonodithioate (125 mg, 1.019 mmol). Themixture was heated to reflux for 3 hours, then it was diluted with water(20 mL) and extracted with CH₂Cl₂ (3×20 mL). The combined organic layerswere dried and concentrated, and the crude mixture was purified bysilica gel chromatography (0-10% MeOH/CH₂Cl₂) to give the title compoundas white solid (385 mg, 82%).

Example 133 Preparation of methyl 2-cyclobutylideneacetate

To a 250 mL round bottom flask was added methyl2-(triphenylphosphoranylidene)acetate (12.04 g, 36 mmol) and benzene (90mL). Cyclobutanone (5.05 g, 72.0 mmol) was added and the solution washeated to reflux for 2 days. The reaction was cooled and hexane (70 mL)was added. The white precipitate was filtered off and the solution wasconcentrated and purified by silica gel chromatography to give the titlecompound as a colorless oil (3.22 g, 71%): IR (thin film) 1714 cm⁻¹; ¹HNMR (400 MHz, CDCl₃) δ 5.60 (t, J=2.3 Hz, 1H), 3.68 (s, 3H), 3.13 (dddd,J=9.0, 4.5, 2.2, 1.1 Hz, 2H), 2.90-2.76 (m, 2H), 2.09 (tt, J=11.4, 5.8Hz, 2H); ¹³C NMR (101 MHz, CDCl₃) δ 167.92, 166.95, 111.93, 50.79,33.71, 32.32, 17.62.

Example 134 Preparation of 2-cyclobutylideneacetic acid

To a solution of methyl 2-cyclobutylideneacetate (100 mg, 0.793 mmol) inMeOH (1.00 mL) stirring at RT was added 2N LiOH solution (prepared fromlithium hydroxide hydrate (100 mg, 2.378 mmol) and water (1 mL)). Themixture was stirred at 25° C. overnight, then it was worked up byaddition of 2N HCl and extracted with CH₂Cl₂. The combined organic layerwas dried to give a white solid, which was purified by silica gelchromatography (0-70% EtOAc/hexane) to give the title compound as awhite solid (20 mg, 23%): IR (thin film) 2923, 1647 cm⁻¹; H NMR (400MHz, CDCl₃) δ 10.89 (s, 1H), 5.60 (dd, J=4.3, 2.1 Hz, 1H), 3.38-3.02 (m,2H), 2.97-2.71 (m, 2H), 2.10 (dq, J=15.9, 8.0 Hz, 2H); ¹³C NMR (101 MHz,CDCl₃) δ 172.35, 171.33, 112.13, 34.10, 32.58, 17.56.

Example 135 Preparation of 3-((3,3,3-trifluoropropyl)thio)propanoic acid

3-Mercaptopropanoic acid (3.2 g, 30.1 mmol) was dissolved in MeOH (20mL) and stirred at RT. Powdered potassium hydroxide (3.72 g, 66.3 mmol)was added to the solution, followed by 3-bromo-1,1,1-trifluoropropane(6.14 g, 34.7 mmol). The solution was then stirred at 65° C. for 3 h andthen the reaction was quenched with 1N HCl until the pH of the solutionwas acidic. The mixture was extracted with CH₂Cl₂ (3×30 mL) and thecombined organic phases were dried, concentrated and purified by silicagel chromatography (0-50% EtOAc/hexane) to give the title compound ascolorless oil mixed with some white suspension (5.5 g, 90%): IR (thinfilm) 2936, 1708 cm⁻¹; H NMR (300 MHz, CDCl₃) δ 2.86-2.78 (m, 2H),2.78-2.58 (m, 4H), 2.52-2.25 (m, 2H); EIMS m/z 202.

Example 136 Preparation ofN-[3-chloro-1-(3-pyridyl)pyrazol-4-yl]-3-[3-[[3-chloro-1-(3-pyridyl)pyrazol-4-yl]-methyl-amino]-3-oxo-propyl]sulfanyl-N-ethyl-2-methyl-propanamide(Compound 790)

To a solution ofN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-2-methyl-3-mercatopropanamide(100 mg, 0.308 mmol) and3-chloro-N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4yl)-N-methylpropanamide(100 mg, 0.334 mmol) in DMF (1 mL) was added sodium hydride (60%dispersion in oil, 15 mg, 0.375 mmol). The mixture was stirred at roomtemperature for 18 h and diluted with water and CH₂Cl₂. The organicphase was separated, dried over Na₂SO₄, filtered and concentrated invacuo to give an orange oil. This oil was purified by chromatographyeluting with mixtures of methanol and methylene chloride to give thetitle compound as a yellow oil (120 mg, 66%).

Example 137 Preparation ofN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-3-((2-((3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)(methyl)amino)-2-oxoethyl)thio)-N-ethylpropanamide(Compound 789)

To a solution ofN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-3-mercaptopropanamide(100 mg, 0.322 mmol) in DMSO (1 mL) was added sodium hydride (60%dispersion in oil, 15 mg, 0.375 mmol). Freshly prepared2-chloro-N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-methylacetamide(150 mg, 0.526 mmol) was added and the mixture was left to stand for onehour with occasional swirling. The reaction mixture was diluted withsaturated sodium bicarbonate and Et₂O. To the organic phase was addedammonia in MeOH (7 M, 1 mL, 1 mmol) followed by Na₂SO₄. After standing10 minutes, the mixture was filtered and concentrated in vacuo to givean orange oil. The oil was purified by silica gel chromatography elutingwith mixtures of methanol and CH₂Cl₂ to give the title molecule as anorange oil (120 mg, 66%).

Example 138 Preparation oftert-butyl((1R,4S)-4-((3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)(methyl)carbamoyl)cyclopent-2-en-1-yl)carbamate

A solution of 3-chloro-N-methyl-1-(pyridin-3-yl)-1H-pyrazol-4-amine (200mg, 0.96 mmol) in THF (10 mL) was cooled to −78° C. Lithiumbis(trimethylsilyl)amide (1 mL, 1.00 mmol, 1M solution in hexane) wasadded and the solution was stirred at −78° C. for 15 minutes. A solutionof (1R,4S)-tert-butyl 3-oxo-2-azabicyclo[2.2.1]hept-5-ene-2-carboxylate(201 mg, 0.96 mmol) dissolved in THF (3 mL) was added to the solution at−78° C. in one portion. After stirring for 1 hour at −78° C. the coolingbath was removed and the reaction warmed to 20° C. After stirring for anadditional five minutes, acetic acid (0.1 mL) was added to the solution.The reaction mixture was concentrated and purified via silica gelchromatography utilizing a mobile phase of hexanes and ethyl acetate togive the title compound as a white solid (250 mg, 59%): ¹H NMR (400 MHz,CDCl₃) δ 9.01-8.93 (d, J=2.8 Hz, 1H), 8.66-8.60 (m, 1H), 8.11-8.02 (m,2H), 7.52-7.42 (m, 1H), 5.93-5.85 (m, 1H), 5.72-5.66 (m, 1H), 5.53-5.44(d, J=9.5 Hz, 1H), 4.80-4.67 (m, 1H), 3.58-3.47 (m, 1H), 3.30-3.21 (s,3H), 2.35-2.22 (m, 1H), 1.90-1.80 (m, 1H), 1.51-1.34 (s, 9H); ¹³C NMR(101 MHz, CDCl₃) δ 175.26, 155.23, 148.70, 140.31, 140.00, 135.61,135.18, 130.99, 126.34, 125.92, 125.78, 124.12, 79.04, 55.69, 47.33,37.49, 35.55, 28.45; ESIMS m/z 418 [M+H]⁺, 416 ([M−H]⁻).

Example 139 Preparation(1S,4R)-4-amino-N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-methylcyclopent-2-enecarboxamide2,2,2-trifluoroacetate

To a solution oftert-butyl((1R,4S)-4-((3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)(methyl)carbamoyl)cyclopent-2-en-1-yl)carbamate(130 mg, 0.31 mmol) in CH₂Cl₂ (4 mL) was added trifluoroacetic acid (4mL). The reaction was left to stand for 20 minutes with occasionalswirling. The reaction mixture was concentrated in vacuo at 40° C.resulting in the isolation of the title compound as a clear oil (130 mg,94%): ¹H NMR (400 MHz, CD₃OD) δ 9.02 (dd, J=2.7, 0.7 Hz, 1H), 8.70 (s,1H), 8.54 (dd, J=5.0, 1.4 Hz, 1H), 8.30 (ddd, J=8.4, 2.7, 1.4 Hz, 1H),7.63 (ddd, J=8.4, 5.0, 0.7 Hz, 1H), 6.09 (ddd, J=5.6, 2.7, 1.0 Hz, 1H),5.92 (dt, J=5.6, 2.1 Hz, 1H), 4.16 (d, J=7.7 Hz, 1H), 3.80-3.72 (m, 1H),2.98 (s, 3H), 2.29 (dt, J=14.3, 7.9 Hz, 1H), 2.01 (dt, J=14.3, 2.5 Hz,1H); ¹³C NMR (101 MHz, CDCl₃) δ 179.16, 163.52 (q, J=19 Hz), 145.04,142.05, 141.15, 137.81, 136.71, 134.11, 134.06, 132.73, 131.26, 129.77,119.49 (q, J=289 Hz) 59.80, 51.85, 40.50, 36.87; ESIMS m/z 318 ([M+H]⁺).

Example 140 Preparation of(1S,4R)—N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-methyl-4-(methylsulfonamido)cyclopent-2-enecarboxamide(Compound Y2054)

To a solution of(1S,4R)-4-amino-N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-methylcyclopent-2-enecarboxamide2,2,2-trifluoroacetate (541 mg, 1.25 mmol) dissolved in CH₂Cl₂ (15 mL)was added triethylamine (0.380 mg, 3.76 mmol) followed bymethanesulfonyl chloride (215 mg, 1.88 mmol). After stirring for 24hours the reaction was diluted with saturated aqueous sodium bicarbonate(15 mL) and the phases were separated. The organic layer was dried withanhydrous sodium sulfate, filtered, and concentrated. The resultingresidue was purified by silica gel chromatography utilizing methanol andCH₂Cl₂ resulting in the isolation of the title compound as a white foam(319 mg, 64%).

Example 141 Preparation of(1S,3R)—N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-methyl-3-(methylsulfonamido)cyclopentanecarboxamide(Compound Y2092)

A solution of(1R,4S)-4-amino-N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-methylcyclopent-2-enecarboxamide2,2,2-trifluoroacetate (60 mg, 0.15 mmol) in methanol (1.5 mL) waspassed through an H-Cube® continuous flow hydrogenator equipped with a10% Pd/C cartridge (full H₂, 25 OC, 1 mL/min flow rate). The resultingsolution was concentrated and purified by silica gel chromatographyutilizing methanol and CH₂Cl₂ as a mobile phase to provide the titlecompound as white solid (16 mg, 24%).

Example 142 Preparation ofN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-3-(1H-tetrazol-5-yl)-N-ethylpropanamide(Compound Y2178)

To a solution ofN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-3-cyano-N-ethylpropanamide(0.176 g, 0.579 mmol) in toluene (5.79 mL) at ambient temperature andunder N₂ were added azidotrimethylsilane (0.154 mL, 1.159 mmol) anddibutylstannanone (0.014 g, 0.058 mmol). The reaction vessel was fittedwith a condenser and heated to 110° C. The reaction was allowed to stirat the same temperature for 24 h at which point UPLC-MS analysisindicated nearly complete conversion to a product of the desired mass.The reaction was cooled, diluted (slowly) in MeOH (20 mL) andconcentrated in vacuo to afford a dark brown oil. The residue wasabsorbed onto Celite and purified via reverse phase flash chromatography(0 to 100% CH₃CN/H₂O) to afford the desired product as a pale brownglassy solid (49 mg, 24%).

Example 143 Preparation ofN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-3-((3,3,3-trifluoro-2-methylpropyl)thio)propanamide(Compound 919)

To a solution ofN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-3-((2-(trifluoromethyl)allyl)thio)propanamide(0.056 g, 0.134 mmol) in DME (2.5 mL) and water (0.5 mL) were added4-methylbenzenesulfonohydrazide (0.249 g, 1.337 mmol) and sodium acetate(0.110 g, 1.337 mmol). The reaction was heated to 90° C. and was stirredfor 1.5 h. UPLC-MS analysis indicated ˜30% conversion to a product ofthe desired mass. The reaction was stirred at 90° C. for an additional1.5 h at which point UPLC-MS analysis indicated ˜75% conversion to aproduct of the desired mass. The reaction was cooled and an additional 5equivalents of both the hydrazide and sodium acetate were added. Thereaction was again heated to 90° C. and stirred for an additional 2 h.UPLC-MS indicated only minor amount of starting material remaining.Therefore, an additional 5 equivalents of both hydrazide and sodiumacetate were added. The reaction was stirred at 90° C. for additional 3h. The reaction was cooled, diluted in EtOAc (10 mL) and washed withwater (2×5 mL) and brine (1×5 mL). The organic layer was dried overNa₂SO₄, filtered and concentrated in vacuo to afford a yellow oil. Thecrude residue was purified via normal phase flash chromatography (0 to100% EtOAc/CH₂Cl₂) to afford the desired product as a pale yellow oil(46 mg, 79%).

Example 144 Preparation ofN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-2-(vinylthio)propanamide(Compound 787)

To a dry round bottom flask under N₂ were added sodium hydride (0.043 g,1.063 mmol, 60% dispersion in mineral oil) and THF (2.126 mL), followedby methanol (0.086 mL, 2.126 mmol). The reaction was allowed to stir atambient temperature until cessation of gas evolution was observed (˜45min). The reaction was then cooled to 0° C. andS-(1-((3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)(ethyl)amino)-1-oxopropan-2-yl)ethanethioate (0.150 g, 0.425 mmol) in THF (2.126 mL) was added. Thereaction was warmed to ambient temperature and stirred for 30 min. Thereaction was again cooled to 0° C. and 1-fluoro-2-iodoethane (0.104 mL,1.275 mmol) in THF (2.126 mL) was added. The reaction was warmed toambient temperature and stirred overnight. The reaction was diluted inEtOAc (5 mL) and quenched with H₂O (1 mL). The layers were separated andthe aqueous layer was extracted with EtOAc (3×10 mL). The combinedorganic extracts were dried over Na₂SO₄, filtered and concentrated invacuo to give a brown oil. The crude residue was purified via flashchromatography (25-80% EtOAc/Hexanes) to give the desired product as anopaque oil (29 mg, 20%).

Example 145 Preparation of(E)-N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-3-((3,3,3-trifluoroprop-1-en-1-yl)thio)propanamide(Compound 890)

To an oven-dried microwave vial under N₂ were added dioxane (0.241 mL),Cu₂O (3.45 mg, 0.024 mmol), KOH (0.0154 g, 0.965 mmol),(E)-1-bromo-3,3,3-trifluoroprop-1-ene (0.563 mL, 4.83 mmol), andN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-3-mercaptopropanamide(0.150 g, 0.483 mmol), sequentially. The reaction was capped and placedon a Biotage® Initiator microwave reactor for 3 h at 110° C., withexternal IR-sensor temperature monitoring from the side of the vessel.During this time, the reaction mixture went from a thick, yellow mixtureto a black mixture. The heterogeneous mixture was cooled to roomtemperature and diluted with EtOAc (20 mL). The mixture was filteredthrough a pad of Celite (EtOAc wash) and the filtrate was concentratedin vacuo to give an dark brown oil. The crude residue was purified vianormal phase flash chromatography (0 to 100% EtOAc/CH₂Cl₂) to afford thedesired product as a pale yellow oil (71 mg, 35%). Reference: Kao,H.-L.; Lee, C.-F. Org. Lett. 2011, 13, 5204-5207.

Example 146 Preparation ofN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-3-(methylsulfonamido)propanamide(Compound Y2145)

To a solution ofN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethylacrylamide (0.538g, 1.944 mmol) in DMF (19.44 mL) at ambient temperature were added K₂CO₃(0.672 g, 4.86 mmol) and methanesulfonamide (0.277 g, 2.92 mmol). Thereaction was fitted with a reflux condenser and heated to 80° C. Afterstirring for 1 h, the reaction was cooled to ambient temperature anddiluted in EtOAc (50 mL) and water (50 mL). The layers were mixedvigorously for 2 min and then separated. The aqueous phase was extractedwith EtOAc (3×50 mL) and the combined organic extracts were washed withbrine (3×100 mL), dried over Na₂SO₄, filtered and concentrated in vacuoto afford a clear oil. The crude residue was purified via normal phaseflash chromatography (0 to 30% MeOH/EtOAc) to afford the desired productas a clear semi-solid (524 mg, 69%).

Example 147 Preparation ofN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-3-(N-(cyanomethyl)methylsulfonamido)-N-methylpropanamide(Compound 803)

To a solution ofN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-methyl-3-(methylsulfonamido)propanamide(0.085 g, 0.238 mmol) in THF (2.376 mL) at 0° C. was added NaH (9.98 mg,0.249 mmol, 60% dispersion in mineral oil). The reaction was allowed tostir for 10 min at which point 2-bromoacetonitrile (0.025 mL, 0.356mmol) was added. The reaction was allowed to warm to room temperatureand was stirred for 1 h. The reaction was quenched with the addition ofwater (5 mL) and was diluted in EtOAc (10 mL). The layers were separatedand the aqueous layer was extracted with EtOAc (3×10 mL). The combinedorganic extracts were dried over Na₂SO₄, filtered and concentrated invacuo. The crude residue was purified via flash chromatography (0 to 10%MeOH/CH₂Cl₂) to give the desired product as a pale yellow foam (86 mg,87%).

Example 148 Preparation ofN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-3-((3,3,3-trifluoropropyl)amino)propanamide

To a microwave vial were added MeOH (2.0 mL),3,3,3-trifluoropropan-1-amine (0.386 g, 3.42 mmol) and3-chloro-N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethylpropanamide(0.107 g, 0.342 mmol), sequentially. The reaction was capped and placedin a Biotage® Initiator microwave reactor for 3 h at 100° C., withexternal IR-sensor temperature monitoring from the side of the vessel.After cooling, the reaction was concentrated in vacuo and purified vianormal phase flash chromatography (0 to 15% MeOH/EtOAc) to afford thedesired product as an opaque viscous oil (127 mg, 94%): ¹H NMR (400 MHz,CDCl₃) δ 8.94 (dd, J=2.8, 0.7 Hz, 1H), 8.63 (dd, J=4.7, 1.5 Hz, 1H),8.04 (ddd, J=8.3, 2.7, 1.4 Hz, 1H), 7.95 (s, 1H), 7.46 (ddd, J=8.4, 4.8,0.8 Hz, 1H), 3.71 (q, J=7.2 Hz, 2H), 2.93-2.80 (m, 4H), 2.35 (t, J=6.2Hz, 2H), 2.28 (ddt, J=14.6, 7.3, 3.6 Hz, 2H), 1.16 (t, J=7.2 Hz, 3H);¹⁹F NMR (376 MHz, CDCl₃) δ-65.13; ESIMS m/z 390 ([M+H]⁺).

N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-3-(methylamino)propanamidewas prepared as in Example 148: ¹H NMR (400 MHz, CDCl₃) δ 9.01 (d, J=2.6Hz, 1H), 8.61 (dd, J=4.8, 1.4 Hz, 1H), 8.23 (s, 1H), 8.06 (ddd, J=8.3,2.7, 1.4 Hz, 1H), 7.45 (dd, J=8.3, 4.8 Hz, 1H), 7.24 (s, 1H), 3.68 (q,J=7.2 Hz, 2H), 3.14 (t, J=6.1 Hz, 2H), 2.71-2.56 (m, 5H), 1.14 (t, J=7.2Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 172.1, 148.6, 140.8, 140.1, 135.6,126.6, 126.3, 124.1, 123.8, 47.1, 43.8, 36.1, 33.5, 13.1; ESIMS m/z 308([M+H]⁺).

N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-3-((4,4,4-trifluorobutyl)amino)propanamidewas prepared as in Example 148: ¹H NMR (400 MHz, CDCl₃) δ 9.04 (d, J=2.7Hz, 1H), 8.61 (dd, J=4.7, 1.5 Hz, 1H), 8.36 (s, 1H), 8.08 (ddd, J=8.4,2.8, 1.5 Hz, 1H), 7.45 (ddd, J=8.4, 4.8, 0.7 Hz, 1H), 3.69 (q, J=7.2 Hz,2H), 3.18 (t, J=6.0 Hz, 2H), 3.02 (t, J=7.7 Hz, 3H), 2.75 (t, J=6.0 Hz,2H), 2.25 (tdt, J=16.1, 10.6, 5.5 Hz, 2H), 2.14-1.98 (m, 2H), 1.16 (t,J=7.2 Hz, 3H); ¹⁹F NMR (376 MHz, CDCl₃) δ-66.03; ESIMS m/z 404 ([M+H]⁺).

N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-3-(ethylamino)propanamidewas prepared as in Example 148: ¹H NMR (400 MHz, CDCl₃) δ 9.05 (s, 1H),8.61 (s, 1H), 8.41 (dd, J=7.6, 2.1 Hz, 1H), 8.09 (dd, J=8.3, 1.4 Hz,1H), 7.44 (dd, J=8.4, 4.8 Hz, 1H), 3.83-3.59 (m, 2H), 3.21 (t, J=6.0 Hz,2H), 3.14-2.97 (m, 2H), 2.86 (s, 2H), 1.52-1.32 (m, 3H), 1.23-1.06 (m,3H); ¹³C NMR (101 MHz, CDCl₃) δ 170.7, 148.5, 140.5, 140.0, 135.6,128.1, 126.4, 124.0, 122.4, 44.0, 43.3, 43.3, 30.1, 12.8, 11.4; ESIMSm/z 322 ([M+H]⁺).

N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-3-(phenylamino)propanamidewas prepared as in Example 148: ¹H NMR (400 MHz, CDCl₃) δ 8.81 (d, J=2.7Hz, 1H), 8.60 (dd, J=4.8, 1.4 Hz, 1H), 7.89 (ddd, J=8.3, 2.7, 1.5 Hz,1H), 7.54 (s, 1H), 7.42 (ddd, J=8.3, 4.8, 0.8 Hz, 1H), 7.17-7.05 (m,2H), 6.64 (tt, J=7.3, 1.1 Hz, 1H), 6.59-6.49 (m, 2H), 4.22 (s, 1H), 3.70(dt, J=14.8, 7.4 Hz, 2H), 3.48 (t, J=6.0 Hz, 2H), 2.45 (t, J=6.2 Hz,2H), 1.14 (t, J=7.1 Hz, 3H); ESIMS m/z 370 ([M+H]⁺).

Example 149 Preparation ofN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-3-(N-(3,3,3-trifluoropropyl)methylsulfonamido)propanamide(Compound 978)

To a solution ofN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-3-((3,3,3-trifluoropropyl)amino)propanamide(0.085 g, 0.218 mmol) in CH₂Cl₂ (2.181 mL) at ambient temperature andunder N₂ were added diisopropylethylamine (0.152 mL, 0.872 mmol) andmethanesulfonyl chloride (0.025 mL, 0.327 mmol). The reaction wasallowed to stir overnight after which the reaction was diluted in CH₂Cl₂(5 mL) and water (3 mL). The phases were mixed and then separated by aphase separator. The organic layer was concentrated in vacuo to afford adark orange oil. The crude product was purified via normal phase flashchromatography (0 to 100% EtOAc/CH₂Cl₂) to afford the desired product asa pale yellow, viscous oil (78 mg, 73%).

Example 150 Preparation ofN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-3-(methyl(3,3,3-trifluoropropyl)amino)propanamide(Compound Y2146)

To a solution ofN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-3-(methylamino)propanamide(0.139 g, 0.452 mmol) in DMF (4.52 mL) at ambient temperature were addedK₂CO₃ (0.125 g, 0.903 mmol) and 3-bromo-1,1,1-trifluoropropane (0.060mL, 0.565 mmol). The reaction was fitted with a condenser, heated to 70OC, and stirred overnight. UPLC-MS analysis indicated the presence ofunreacted starting material. Therefore, an additional 3 equivalents of3-bromo-1,1,1-trifluoropropane were added and reaction was left to stirat 70° C. for 3 h. UPLC-MS analysis indicated complete consumption ofstarting material and conversion to product of the desired mass. Thereaction was cooled, diluted in EtOAc (20 mL) and filtered through a padof Celite. The filtrate was then washed with half-saturated brine (3×20mL), dried over Na₂SO₄, filtered and concentrated in vacuo. The cruderesidue was purified via normal phase flash chromatography (0 to 15%MeOH/CH₂Cl₂) to afford the desired product as a clear oil (84 mg, 44%).

Example 151 Preparation ofN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-3-((3-oxobutyl)thio)propanamide(Compound 877)

To a solution of but-3-en-2-one (0.040 mL, 0.444 mmol) in water (0.370mL) and dioxane (0.370 mL) was addedN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-3-mercaptopropanamide(0.115 g, 0.370 mmol) at ambient temperature. The reaction was allowedto stir for 1 h at which point the reaction was diluted in CH₂Cl₂ andthe mixture was stirred vigorously for 1 h. The mixture was then passedthrough a phase separator and the remaining aqueous phase was washedwith CH₂Cl₂ (3×5 mL). The combined organic extracts were concentrated invacuo to provide the desired product as an orange oil that wasanalytically pure by ¹H NMR and UPLC-MS analyses (140 mg, 94%).Reference: Khatik, G. L.; Kumar, R.; Chakraborti, A. K. Org. Lett. 2006,8, 2433-2436.

Example 152 Preparation ofN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-3-((3,3-difluorobutyl)thio)-N-ethylpropanamide(Compound 889)

To a solution ofN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-3-((3-oxobutyl)thio)propanamide(0.184 g, 0.483 mmol) in CH₂Cl₂ (4.83 mL) at 0° C. was addedDeoxo-Fluor® (0.534 mL, 2.90 mmol) followed by EtOH (0.017 mL, 0.290mmol). The reaction was stirred at ambient temperature for 48 h duringwhich time the solution went from pale yellow to dark brown. Thereaction was diluted in CH₂Cl₂ (10 mL) and quenched with the carefuladdition of NaHCO_(3(aq)) (5 mL). The layers were separated and theaqueous phase was extracted with CH₂Cl₂ (3×10 mL). The combined organicextracts were dried over Na₂SO₄, filtered and concentrated in vacuo. Thecrude residue was purified via normal phase flash chromatography (0 to100% EtOAc/CH₂Cl₂) to afford the desired product as a pale yellow oil(43 mg, 21%).

Example 153 Preparation ofN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-3-((3,3-difluoropropyl)thio)-N-ethylpropanamide(Compound 927)

To a solution ofN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-3-((3,3-dimethoxypropyl)thio)-N-ethylpropanamide(0.307 g, 0.743 mmol) in THF (7.43 mL) was added a 1.0 M aqueoussolution of HCl (7.43 mL, 7.43 mmol). The reaction was allowed to stirat ambient temperature for 1 h at which point TLC/UPLC-MS analysisindicated complete hydrolysis to the desired aldehyde product hadoccurred. The mixture was diluted in EtOAc (20 mL) and water (10 mL).The layers were mixed, separated, and the aqueous layer was extractedwith EtOAc (3×20 mL). The combined organic extracts were washed withNaHCO₃ (1×25 mL), water (1×25 mL) and brine (1×25 mL) and then driedover Na₂SO₄, filtered and concentrated in vacuo. The crude product wasdried via azeotropic distillation from toluene (3×10 mL) and then placedunder N₂. To the flask was added CH₂Cl₂ (7.44 mL) and the solution wascooled to 0° C. Deoxo-Fluor® (0.686 mL, 3.72 mmol) and EtOH (4.34 μl,0.074 mmol) were added and the reaction was warmed to ambienttemperature. After 18 h, the reaction was diluted in CH₂Cl₂ (10 mL) andquenched with the careful addition of NaHCO_(3(aq)) (5 mL). The layerswere separated and the aqueous phase was extracted with CH₂Cl₂ (3×10mL). The combined organic extracts were dried over Na₂SO₄, filtered andconcentrated in vacuo. The crude material was purified via normal phaseflash chromatography (0 to 100% EtOAc/CH₂Cl₂) to afford the desiredproduct as a pale yellow oil (151 mg, 50%).

Example 154 Preparation of 1,1,1-trifluoro-3-iodo-5-methylhexane

To a microwave vial equipped with a magnetic stir bar were added water(5.94 mL), acetonitrile (5.94 mL), sodium dithionite (0.569 g, 3.27mmol), sodium bicarbonate (0.499 g, 5.94 mmol), and 4-methylpent-1-ene(0.379 mL, 2.97 mmol). The vessel was sealed with a microwave cap(crimped), cooled to −78° C. and evacuated under house vacuum. Next,trifluoroiodomethane (0.873 g, 4.46 mmol) (approximate) was condensedinto the reaction vessel. After warming to ambient temperature, thereaction was stirred for 2.5 h. Prior to removing the cap, the reactionwas vented with a needle and substantial gas evolution was observed. Thereaction was then diluted in water (5 mL) and the mixture was extractedwith Et₂O (3×20 mL) and the combined extracts were dried over MgSO₄,filtered and concentrated in vacuo to afford a clear oil (740 mg, 80%).Crude ¹H NMR analysis indicated desired product to be of ˜90% purity.Product was therefore used in subsequent reactions without furtherpurification: ¹H NMR (400 MHz, CDCl₃) δ 4.25-4.06 (m, 1H), 2.94 (dqd,J=15.5, 10.6, 6.1 Hz, 1H), 2.77 (dqd, J=15.5, 10.0, 7.5 Hz, 1H),1.92-1.74 (m, 2H), 1.45-1.28 (m, 1H), 0.98 (d, J=6.5 Hz, 3H), 0.87 (d,J=6.5 Hz, 3H); ¹⁹F NMR (376 MHz, CDCl₃) δ-63.63. Reference: Ignatowska,J.; Dmowski, W. J. Fluor. Chem., 2007, 128, 997-1006.

(4,4,4-trifluoro-2-iodobutyl)benzene was prepared as in Example 154: ¹HNMR (400 MHz, CDCl₃) δ 7.41-7.27 (m, 3H), 7.23-7.16 (m, 2H), 4.33 (dq,J=8.2, 6.7 Hz, 1H), 3.31-3.15 (m, 2H), 2.96-2.72 (m, 2H); ¹⁹F NMR (376MHz, CDCl₃) δ-63.63; EIMS m/z 314.

1-(4,4,4-trifluoro-2-iodobutyl)-1H-imidazole was prepared as in Example154: ¹H NMR (400 MHz, CDCl₃) δ 7.61 (t, J=1.1 Hz, 1H), 7.12 (t, J=1.1Hz, 1H), 7.00 (t, J=1.4 Hz, 1H), 4.46-4.31 (m, 3H), 2.88-2.66 (m, 2H);¹⁹F NMR (376 MHz, CDCl₃) δ-63.57; EIMS m/z 304.

1,1,1-trifluoro-3-iodopentane was prepared as in Example 154: ¹H NMR(400 MHz, CDCl₃) δ 4.20 (tdd, J=7.9, 6.2, 4.4 Hz, 1H), 3.01-2.84 (m,1H), 2.84-2.69 (m, 1H), 1.84-1.74 (m, 2H), 1.06 (t, J=7.1 Hz, 3H); ¹⁹FNMR (376 MHz, CDCl₃) δ-64.06; EIMS m/z 252.

Example 155 Preparation ofS-(1,1,1-trifluoro-5-methylhexan-3-yl)benzothioate

To a solution of 1,1,1-trifluoro-3-iodo-5-methylhexane (0.047 g, 0.168mmol) in DMF (1.678 mL) at ambient temperature was added potassiumbenzothioate (0.035 g, 0.201 mmol). The reaction was allowed to stir for18 h at which point the reaction was diluted in water (3 mL) and EtOAc(5 mL). The layers were mixed and then separated. The aqueous layer wasextracted with EtOAc (3×5 mL) and the combined organic extracts werewashed with water (1×10 mL) and half saturated brine (2×10 mL), driedover Na₂SO₄, filtered and concentrated in vacuo. Residue was purifiedvia flash chromatography (0 to 30% EtOAc/Hexanes) to afford the desiredproduct as a clear oil (37 mg, 68%): ¹H NMR (400 MHz, CDCl₃) δ 7.99-7.92(m, 2H), 7.62-7.55 (m, 1H), 7.50-7.41 (m, 2H), 4.10-3.95 (m, 1H),2.73-2.56 (m, 1H), 2.56-2.40 (m, 1H), 1.94-1.73 (m, 1H), 1.73-1.61 (m,2H), 0.97 (d, J=6.6 Hz, 3H), 0.94 (d, J=6.5 Hz, 3H); ¹⁹F NMR (376 MHz,CDCl₃) δ-62.89.

S-(4,4,4-trifluoro-1-phenylbutan-2-yl)benzothioate was prepared as inExample 155: ¹H NMR (400 MHz, CDCl₃) δ 7.97-7.89 (m, 2H), 7.58 (ddt,J=7.9, 6.9, 1.3 Hz, 1H), 7.49-7.41 (m, 2H), 7.39-7.26 (m, 5H), 4.29-4.15(m, 1H), 3.11 (d, J=7.2 Hz, 2H), 2.54 (qd, J=10.6, 6.6 Hz, 2H); ¹⁹F NMR(376 MHz, CDCl₃) δ-62.86; EIMS m/z 324.

S-(4,4,4-trifluoro-1-(1H-imidazol-1-yl)butan-2-yl)benzothioate wasprepared as in Example 155: ¹H NMR (400 MHz, CDCl₃) δ 7.98-7.89 (m, 2H),7.68-7.60 (m, 1H), 7.56 (t, J=1.1 Hz, 1H), 7.53-7.45 (m, 2H), 7.11 (t,J=1.1 Hz, 1H), 7.05 (t, J=1.3 Hz, 1H), 4.42-4.18 (m, 3H), 2.64-2.39 (m,2H); ¹⁹F NMR (376 MHz, CDCl₃) δ-62.98; EIMS m/z 314.

S-(1,1,1-trifluoropentan-3-yl)benzothioate was prepared as in Example155: ¹H NMR (400 MHz, CDCl₃) δ 8.02-7.91 (m, 2H), 7.64-7.55 (m, 1H),7.51-7.40 (m, 2H), 4.06-3.90 (m, 1H), 2.70-2.41 (m, 2H), 2.02-1.86 (m,1H), 1.86-1.71 (m, 1H), 1.05 (t, J=7.3 Hz, 3H); ¹⁹F NMR (376 MHz, CDCl₃)δ-63.32; EIMS m/z 262.

Example 156 Preparation ofN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-3-((1,1,1-trifluoro-5-methylhexan-3-yl)thio)propanamide(Compound 1053)

To a suspension of NaH (60% in mineral oil, 0.012 g, 0.300 mmol) in THF(2.86 mL) at ambient temperature and under N₂ was added MeOH (0.058 mL,1.429 mmol). The reaction became homogenous and gas evolution wasobserved. After stirring for 30 min, the reaction was cooled to 0° C.and a solution of S-(1,1,1-trifluoro-5-methylhexan-3-yl)benzothioate(0.083 g, 0.286 mmol) in THF (2 mL) was added slowly. The reaction waswarmed to ambient temperature, stirred for 45 min, and then returned to0° C. To the reaction was added a solution of3-chloro-N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethylpropanamide(0.090 g, 0.286 mmol) in THF (2 mL). The reaction was warmed to ambienttemperature and stirred for 18 h. The reaction was diluted in EtOAc (20mL) and water (10 mL). The layers were mixed and then separated. Theaqueous layer was extracted with EtOAc (3×20 mL) and the combinedorganic extracts were dried over Na₂SO₄, filtered and concentrated invacuo. The crude residue was purified via normal phase flashchromatography (0 to 100% EtOAc/CH₂Cl₂) to afford the desired product asa pale yellow oil (63 mg, 45%).

Example 157 Preparation oftert-butyl(2-(2,2-difluorocyclopropyl)ethoxy)diphenylsilane

To an oven-dried 3-neck round bottom flask equipped with refluxcondenser and addition funnel under N₂ were added(but-3-en-1-yloxy)(tert-butyl)diphenylsilane (3.6 g, 11.59 mmol) andsodium fluoride (7.30 mg, 0.174 mmol) (For preparation of startingolefin, see: Waser, J.; Gaspar, B.; Nambu, H.; Carreira, E. M. J. Am.Chem. Soc. 2006, 128, 11693-11712). To the closed addition funnel wasadded trimethylsilyl 2,2-difluoro-2-(fluorosulfonyl)acetate (4.57 mL,23.19 mmol). The reaction vessel and its contents were heated to 120° C.and the addition funnel was then opened to allow the sulfonyl fluorideto add over 1 h. Once the addition was complete, the reaction wasallowed to continue stirring at 120° C. for 30 min. The reaction wascooled to ambient temperature, diluted in CH₂Cl₂ (50 mL) and washed withNaHCO_(3(aq)) (2×50 mL). The organic phase was separated, dried overNa₂SO₄, filtered and concentrated in vacuo to provide a brown oil. Thecrude residue was purified via normal phase flash chromatography (0 to15% CH₂Cl₂/Hexanes) to provide the desired product as a clear oil (3.07g, 73%): ¹H NMR (400 MHz, CDCl₃) δ 7.72-7.63 (m, 4H), 7.49-7.34 (m, 6H),3.73 (t, J=6.0 Hz, 2H), 1.88-1.73 (m, 1H), 1.73-1.55 (m, 2H), 1.42-1.27(m, 1H), 1.06 (s, 9H), 0.94-0.81 (m, 1H); ¹⁹F NMR (376 MHz, CDCl₃)δ-128.54 (d, J=156.2 Hz), −143.96 (d, J=155.5 Hz); ¹³C NMR (101 MHz,CDCl₃) δ 135.5, 133.7 (d, J=3.7 Hz), 129.6, 127.7, 114.5, 62.8, 30.0 (d,J=3.5 Hz), 26.8, 19.9 (t, J=10.9 Hz), 19.2, 15.9 (t, J=11.0 Hz).

Example 158 Preparation of 2-(2,2-difluorocyclopropyl)ethyl4-methylbenzenesulfonate

To a solution oftert-butyl(2-(2,2-difluorocyclopropyl)ethoxy)diphenylsilane (0.386 g,1.071 mmol) in THF (10.71 mL) at 0° C. was added a 1.0 M solution ofTBAF (3.21 mL, 3.21 mmol) in THF. The reaction was warmed to ambienttemperature and stirred for 3 h. The reaction was quenched with theaddition of NH₄Cl_((aq)) (1 mL) and the mixture was partitioned betweenwater (15 mL) and EtOAc (15 mL). The layers were mixed well and thenseparated. The aqueous layer was extracted with EtOAc (3×20 mL) and thecombined organic extracts were dried over Na₂SO₄, filtered andconcentrated in vacuo. The crude residue was then taken up in CH₂Cl₂(7.15 mL). To the solution were then added pyridine (0.434 mL, 5.36mmol) and p-toluenesulfonyl chloride (0.614 g, 3.22 mmol). The reactionwas stirred at ambient temperature for 48 h at which point the reactionwas partitioned between CH₂Cl₂ (50 mL) and water (25 mL). The layerswere separated and the organic layer was washed with 1N HCl_((aq)) (20mL), water (20 mL) and brine (20 mL). The organic layer was then driedover Na₂SO₄, filtered and concentrated in vacuo. The crude residue waspurified via normal phase flash chromatography (0 to 50% EtOAc/Hexanes)to afford the desired product as a clear oil (142 mg, 46%, 2 steps): ¹HNMR (400 MHz, CDCl₃) δ 7.89-7.71 (m, 2H), 7.42-7.29 (m, 2H), 4.20-3.96(m, 2H), 2.46 (s, 3H), 1.92-1.81 (m, 1H), 1.81-1.69 (m, 1H), 1.63-1.48(m, 1H), 1.39 (dddd, J=12.2, 11.2, 7.7, 4.3 Hz, 1H), 0.93 (dtd, J=13.0,7.6, 3.5 Hz, 1H); ¹³C NMR (101 MHz, CDCl₃) δ 145.0, 132.9, 129.9, 127.9,113.5 (t, J=282.4 Hz), 69.0 (d, J=2.2 Hz), 26.6 (d, J=4.3 Hz), 21.7,18.9 (t, J=11.1 Hz), 15.9 (t, J=11.0 Hz); ¹⁹F NMR (376 MHz, CDCl₃)δ-129.09 (d, J=157.8 Hz), −144.18 (d, J=158.1 Hz).

Example 159 Preparation ofN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-methylacrylamide(Compound Y2098)

To a solution of 3-chloro-N-methyl-1-(pyridin-3-yl)-1H-pyrazol-4-amine(0.526 g, 2.52 mmol) in 1,2-dichloroethane (25.2 mL) at 0° C. were addeddiisopropylethylamine (0.484 mL, 2.77 mmol) and acryloyl chloride (0.205mL, 2.52 mmol). The reaction was allowed to warm to ambient temperatureand was stirred for 1 h. The reaction was quenched with the addition ofNaHCO_(3(aq)) and was diluted with CH₂Cl₂. The layers were separated andthe aqueous layer was extracted with CH₂Cl₂. The combined organicextracts were dried over Na₂SO₄, filtered and concentrated in vacuo. Thecrude product was purified via flash chromatography (0 to 10%MeOH/CH₂Cl₂) to give the desired product as an orange solid (634 mg,91%).

Example 160 Preparation ofN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-3-((3,3,3-trifluoropropyl)thio)propanamide(Compound 653)

To a solution of 3-chloro-N-ethyl-1-(pyridin-3-yl)-1H-pyrazol-4-amine(10 g, 44.9 mmol) in CH₂Cl₂ (100 mL) at 0° C. and under N₂ were addedpyridine (5.45 mL, 67.4 mmol), 4-dimethylaminopyridine (DMAP) (2.74 g,22.45 mmol), and 3-((3,3,3-trifluoropropyl)thio)propanoyl chloride (9.91g, 44.9 mmol), sequentially. The reaction was warmed to ambienttemperature and stirred for 1 h. The reaction was poured into water (100mL) and the resulting mixture was stirred for 5 min. The mixture wastransferred to a separatory funnel and the layers were separated. Theaqueous phase was extracted with CH₂Cl₂ (3×50 mL) and the combinedorganic extracts were dried over Na₂SO₄, filtered and concentrated invacuo. The crude product was purified via normal phase flashchromatography (0 to 100% EtOAc/CH₂Cl₂) to afford the desired product asa pale yellow solid (17.21 g, 89%).

Example 161 Preparation ofN-(1-(5-fluoropyridin-3-yl)-3-methyl-1H-pyrazol-4-yl)-2-oxooxazolidine-3-carbothioamide(Compound Y2032)

To a solution of 1-(5-fluoropyridin-3-yl)-3-methyl-1H-pyrazol-4-amine(0.10 g, 0.52 mmol) and triethylamine (0.24 mL, 1.71 mmol) in dry THF(0.52 mL) was added carbon disulfide (0.03 mL, 0.52 mmol) via syringeover 15 minutes. After stirring for 1 hour, the mixture was cooled in anice bath and 4-methylbenzene-1-sulfonyl chloride (0.11 g, 0.57 mmol) wasadded in one portion, stirred for 5 minutes at 0° C. and then warmed to25° C. and stirred for 1 hour. The reaction mixture was quenched with 1NHCl and extracted with diethyl ether. The ether layers were combined,washed with water and half saturated aqueous sodium bicarbonate, dried(MgSO₄), filtered and concentrated to dryness to give the desiredisothiocyanate (0.12 g, 98%). To a solution of oxazolidin-2-one (0.05 g,0.61 mmol) dissolved in dry DMF (2.05 mL) was added sodium hydride (0.03g, 0.61 mmol, 60% dispersion in mineral oil) in one portion and thesuspension was stirred for 20 minutes. The reaction mixture was cooledto 0° C. and3-fluoro-5-(4-isothiocyanato-3-methyl-1H-pyrazol-1-yl)pyridine (0.12 g,0.51 mmol) was added in one portion in a minimum amount of dry DMF andstirred for 20 minutes. Water and ethyl acetate were added and theresulting biphasic mixture was separated and the aqueous layer wasextracted one time with ethyl acetate. The combined organic extractswere washed with 1:1 hexanes/water, dried (MgSO₄), filtered andconcentrated to dryness. The crude product was purified by silica gelchromatography eluting with 0-75% ethyl acetate/hexanes to give thedesired product as a white solid (0.03 g, 18%).

Example 162 Preparation of3-(4-isothiocyanato-3-methyl-1H-pyrazol-1-yl)pyridine

To a solution of 3-methyl-1-(pyridin-3-yl)-1H-pyrazol-4-amine (0.50 g,2.87 mmol) and triethylamine (1.3 mL, 1.71 mmol) in dry THF (2.8 mL) wasadded carbon disulfide (0.17 mL, 2.87 mmol) via syringe over 15 minutes.After stirring for 1 hour, the mixture was cooled in an ice bath and4-methylbenzene-1-sulfonyl chloride (0.60 g, 0.3.16 mmol) was added inone portion, stirred for 5 minutes at 0° C. and then warmed to 25° C.and stirred for 1 hour. The reaction mixture was quenched with 1N HCland extracted with diethyl ether. The ether layers were combined, washedwith water and half saturated aqueous NaHCO₃, dried (MgSO₄), filteredand concentrated to dryness. The crude material was purified by silicagel chromatography eluting with 0-100% ethyl acetate/hexanes to give thedesired product as a light yellow solid (0.48 g, 78%): ¹H NMR (400 MHz,CDCl₃) δ 8.89 (d, J=2.6 Hz, 1H), 8.56 (dd, J=4.7, 1.4 Hz, 1H), 7.96(ddd, J=8.3, 2.7, 1.5 Hz, 1H), 7.89 (s, 1H), 7.40 (ddd, J=8.3, 4.8, 0.7Hz, 1H), 2.40 (s, 3H); ESIMS m/z 218 ([M+H]⁺).

Example 163 Preparation ofN-(3-methyl-1-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-oxooxazolidine-3-carbothiamide(Compound Y2034)

To a solution of oxazolidin-2-one (0.06 g, 0.66 mmol) dissolved in dryDMF (2.2 mL) was added sodium hydride (0.03 g, 0.67 mmol, 60% dispersionin mineral oil) in one portion and the suspension was stirred for 20minutes. The reaction mixture was cooled to 0° C. and3-(4-isothiocyanato-3-methyl-1H-pyrazol-1-yl)pyridine (0.12 g, 0.56mmol) was added in one portion in a minimum amount of dry DMF andstirred for 20 minutes. Water and ethyl acetate were added and theresulting biphasic mixture was separated and the aqueous layer wasextracted one time with ethyl acetate. The combined organic extractswere washed with 1:1 hexanes/water, dried (MgSO₄), filtered andconcentrated to dryness. The crude product was purified by silica gelchromatography eluting with 0-75% ethyl acetate/hexanes to give thedesired product as a white solid (0.07 g, 41%).

Example 164 Preparation of methylN-(3-methyl-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-2-oxooxazolidine-3-carbimidothioate(Compound Y2035)

To a solution of oxazolidin-2-one (0.05 g, 0.66 mmol) dissolved in dryDMF (2.22 mL) was added sodium hydride (0.03 g, 0.66 mmol, 60%dispersion in mineral oil) in one portion and the suspension was stirredfor 20 minutes. The reaction mixture was cooled to 0° C. and3-(4-isothiocyanato-3-methyl-1H-pyrazol-1-yl)pyridine (0.12 g, 0.55mmol) was added in one portion in a minimum amount of dry DMF andstirred for 20 minutes. Iodomethane (0.04 mL, 0.66 mmol) was added andthe reaction was monitored by TLC. Aqueous ammonium chloride and 50%ethyl acetate/hexanes were added and the resulting biphasic mixture wasseparated and the organic extract washed with water and saturatedaqueous sodium bicarbonate and concentrated to dryness. The crudeproduct was purified by silica gel chromatography eluting with 0-10%methanol/CH₂Cl₂ to give the desired product as a light yellow solid(0.14 g, 82%).

Example 165 Preparation ofN-acetyl-N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)cyclopropanecarboxamide(Compound Y2060)

To a solution ofN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)cyclopropanecarboxamide(0.15 g, 0.57 mmol) in dichloroethane (2.5 mL) was addeddiisopropylethylamine (0.12 mL, 0.68 mmol) followed by acetyl chloride(0.54 g, 0.68 mmol) and the reaction was stirred at room temperatureovernight. Saturated aqueous NaHCO₃ was added and the mixture wasextracted with CH₂Cl₂. The combined organic phases were concentrated todryness and purified by silica gel chromatography eluting with 0-100%ethyl acetate/hexanes to give the desired product as a white solid (10mg, 6%).

Example 166 Preparation ofS-methyl(3-chloro-5-(methylthio)-1-(pyridin-3-yl)-1H-pyrazol-4-yl)(ethyl)carbamothioate(Compound Y2076)

To a solution of THF (1.35 mL) and diisopropylethylamine (0.07 mL, 0.40mmol) was added 2.5M n-butyllithium (0.16 mL, 0.40 mmol) and thereaction was stirred for 30 minutes. The reaction was cooled further to−78° C. and to this was added dropwiseS-methyl(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)(ethyl)carbamothioate(0.10 g, 0.33 mmol) in a minimum amount of dry THF and stirred for 45minutes. To this was then added 1,2-dimethyldisulfane (0.04 g, 0.37mmol) and the reaction was stirred for additional 20 minutes. Thereaction was poured into water and extracted with ethyl acetate. Theethyl acetate layers were combined, dried (MgSO₄), filtered andconcentrated to dryness. The crude product was purified by silica gelchromatography eluting with 0-100% ethyl acetate/hexanes to give thedesired product as a clear oil (53 mg, 46%).

Example 167 Preparation ofN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-3-(3,3,3-trifluoropropyl)thio)propanamide(Compound 653)

To a solution ofN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-3-mercaptopropanamide(0.10 g, 0.32 mmol) dissolved in dry THF (1.07 mL) and cooled in an icebath was added sodium hydride (0.02 g, 0.34 mmol, 60% dispersion inmineral oil) in one portion and the reaction was stirred for 10 minutes.To this was added 3-bromo-1,1,1-trifluoropropane (0.06 g, 0.35 mmol) inone portion in a minimum amount of dry DMF and the reaction was stirredat room temperature for 2 hours. The reaction mixture was poured intowater and extracted with ethyl acetate. The ethyl acetate layers werecombined and concentrated to dryness. The crude product was purified bysilica gel chromatography eluting with 0-75% ethyl acetate hexanes togive the desired product as a clear oil (83 mg, 63%).

Example 168 Preparation oftert-butyl(2-((3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)(ethyl)amino)-2-oxoethyl)(methyl)carbamate

To a solution of 3-chloro-N-ethyl-1-(pyridin-3-yl)-1H-pyrazol-4-amine(0.40 g, 1.79 mmol) in dichloroethane (3.59 mL) was added2-((tert-butoxycarbonyl)(methyl)amino)acetic acid (0.37 g, 1.97 mmol),4-N,N-dimethylaminopyridine (0.24 g, 1.97 mmol) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.51 g,2.69 mmol) and the reaction was stirred overnight at room temperature.The reaction mixture was concentrated to dryness and the crude productwas purified by silica gel chromatography eluting with 0-100% ethylacetate/hexanes to give the desired product as a white semi solid (0.61g, 87%): IR (thin film) 1673 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 8.96 (d,J=2.4 Hz, 1H), 8.63 (dd, J=5.3 Hz, 1H), 8.11-7.86 (m, 2H), 7.51-7.36 (m,1H), 3.92-3.57 (m, 4H), 2.96-2.81 (m, 3H), 1.50-1.37 (s, 9H), 1.20-1.11(m, 3H); ESIMS m/z 394 ([M+H]⁺).

The following molecules were made in accordance with the proceduresdisclosed in Example 168:

tert-Butyl(2-((3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)(methyl)amino)-2-oxoethyl)(methyl)carbamate:¹H NMR (400 MHz, CDCl₃) δ 8.95 (d, J=2.5 Hz, 1H), 8.62 (d, J=4.8 Hz,1H), 8.14-7.84 (m, 2H), 7.59-7.35 (m, 1H), 3.85 (d, J=25.9 Hz, 2H),3.31-3.15 (m, 3H), 2.99-2.81 (m, 3H), 1.53-1.31 (s, 9H).

tert-Butyl(2-((3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)(cyclopropylmethyl)amino)-2-oxoethyl)(methyl)carbamate:IR (thin film) 1675 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 8.95 (bs, 1H), 8.63(dd, J=5.1 Hz, 1H), 8.17-7.88 (m, 2H), 7.54-7.36 (m, 1H), 3.99-3.41 (m,4H), 2.97-2.82 (m, 3H), 1.44 (s, 9H), 1.12-0.83 (m, 1H), 0.59-0.39 (m,2H), 0.28-0.08 (m, 2H); ESIMS m/z 420 ([M+H]⁺).

Example 169 Preparation ofN-(3-chloro-1-pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-2-(methylamino)acetamide

To a solution oftert-butyl(2-((3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)(ethyl)amino)-2-oxoethyl)(methyl)carbamate(0.57 g, 1.44 mmol) in CH₂Cl₂ (1.44 mL) was added trifluoroacetic acid(1.44 mL) and the reaction was stirred at room temperature for 1 hour.Toluene was added and the reaction was concentrated to near dryness. Themixture was poured into a separatory funnel containing saturated aqueousNaHCO₃ and was extracted with CH₂Cl₂. The CH₂Cl₂ layers were combinedand concentrated to dryness. The crude product was purified by silicagel chromatography eluting with 0-15% methanol/CH₂Cl₂ to give thedesired product as a yellow oil (0.31 g, 73%): IR (thin film) 1666 cm⁻¹;¹H NMR (400 MHz, CDCl₃) δ 8.98 (d, J=2.6 Hz, 1H), 8.63 (dd, J=4.7, 1.3Hz, 1H), 8.06 (m, 2H), 7.47 (dd, J=8.3, 4.8 Hz, 1H), 3.72 (q, J=7.1 Hz,2H), 3.30 (s, 2H), 2.48 (s, 3H), 1.17 (t, J=7.2 Hz, 3H); ESIMS m/z 294([M+H]⁺).

The following compounds were made in accordance with the proceduresdisclosed in Example 169:

N-(3-Chloro-1-(pyridin-3-yl)-H-pyrazol-4-yl)-N-methyl-2-(methylamino)acetamide:IR (thin film) 1666 cm⁻¹; H NMR (400 MHz, CDCl₃) δ 8.96 (d, J=2.6 Hz,1H), 8.64 (dd, J=4.8, 1.3 Hz, 1H), 8.11-7.94 (m, 2H), 7.47 (dd, J=8.4,4.4 Hz, 1H), 3.30 (s, 2H), 3.27 (s, 3H), 2.47 (s, 3H); ESIMS m/z 280([M+H]⁺).

N-(3-Chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-(cyclopropylmethyl)-2-(methylamino)acetamide:IR (thin film) 1667 cm⁻¹; H NMR (400 MHz, CDCl₃) δ 8.98 (d, J=2.6 Hz,1H), 8.63 (dd, J=4.7, 1.3 Hz, 1H), 8.11 (s, 1H), 8.06 (ddd, J=8.3, 2.7,1.4 Hz, 1H), 7.47 (dd, J=8.3, 4.8 Hz, 1H), 3.53 (bs, 2H), 3.27 (bs, 2H),2.49 (s, 3H), 1.02-0.91 (m, 1H), 0.55-0.44 (m, 2H), 0.22-0.15 (m, 2H);ESIMS m/z 320 ([M+H]⁺).

Example 170 Preparation ofN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-2-(N-methylmethylsulfonamido)acetamide(Compound 800)

To a solution ofN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-2-(methylamino)acetamide(0.10 g, 0.34 mmol) in CH₂Cl₂ (0.68 mL) was added methanesulfonylchloride (0.06 g, 0.51 mmol) followed by diisopropylethylamine (0.12 mL,0.68 mmol) and the reaction was stirred overnight at room temperature.The reaction mixture was poured into saturated aqueous NaHCO₃ andextracted with CH₂Cl₂. The CH₂Cl₂ layers were combined and concentratedto dryness. The crude product was purified by silica gel chromatographyeluting with 50-100% ethyl acetate/hexanes to give the desired productas a white semi-solid (81 mg, 64%).

Example 171 Preparation ofN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-3-((3,3,3-trifluoropropyl)sulfinyl)propanamide(Compound 861)

Method A: ToN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-3-((3,3,3-trifluoropropyl)thio)propanamide(0.17 g, 0.43 mmol) in glacial acetic acid (4.35 mL) was added sodiumperborate tetrahydrate (0.07 g, 0.45 mmol), and the mixture was heatedat 55° C. for 1 hour. The reaction mixture was carefully poured into aseparatory funnel containing saturated aqueous NaHCO₃ resulting in gasevolution. When the gas evolution had ceased, ethyl acetate was addedand the layers were separated. The aqueous layer was extracted twicewith ethyl acetate, and the organic layers were combined, dried overMgSO₄, filtered and concentrated under reduced pressure. The crudematerial was purified by silica gel chromatography eluting with 0-5%methanol/CH₂Cl₂ to give the desired product as a dark oil (60 mg, 33%).

Method B: To a solution ofN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-3-((3,3,3-trifluoropropyl)thio)propanamide(500 mg, 1.229 mmol) in hexafluoroisopropanol (5 mL) stirring at roomtemperature was added 30% hydrogen peroxide (523 mg, 4.92 mmol). Thesolution was stirred at room temperature for 15 min. It was quenchedwith saturated sodium sulfite solution and extracted with CH₂Cl₂. Silicagel chromatography (0-10% MeOH/CH₂Cl₂) gave the title compound as whitesemi-solid (495 mg, 95%).

Example 172 Preparation ofN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-2-(methylamino)propanamide

2-chloro-N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethylpropanamide(0.51 g, 1.62 mmol) and methylamine (4.05 mL, 32.6 mmol, 33% in ethanol)were placed in a 25 mL vial on a Biotage® Initiator microwave reactorfor 45 minutes at 100° C., with external IR-sensor temperaturemonitoring from the side of the vessel. The reaction was concentrated todryness and purified by silica gel chromatography (0-10% methanol/CH₂Cl₂to give the desired product as a yellow solid (0.21 g, 43%): ¹H NMR (400MHz, CDCl₃) δ 8.96 (d, J=2.6 Hz, 1H), 8.64 (dd, J=4.7, 1.3 Hz, 1H), 8.06(ddd, J=8.3, 2.7, 1.4 Hz, 1H), 7.98 (s, 1H), 7.47 (dd, J=8.3, 4.8 Hz,1H), 3.93-3.57 (m, 2H), 3.25-3.11 (m, 1H), 2.34 (s, 3H), 1.21-1.17 (m,6H).

The following compound was made in accordance with the proceduresdisclosed in Example 172:

N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-3-(methylamino)propanamide

¹H NMR (400 MHz, Acetone) δ 9.12 (dd, J=6.7, 2.6 Hz, 1H), 8.90 (s, 1H),8.58 (dd, J=4.7, 1.4 Hz, 1H), 8.25 (m, 1H), 7.56 (m, 1H), 3.67 (q, J=7.1Hz, 2H), 3.01 (t, J=6.5 Hz, 2H), 2.66 (t, J=6.4 Hz, 2H), 2.50 (s, 3H),1.12 (t, J=7.2 Hz, 3H); LC/MS (ESI) m/z 308.4 ([M+H]⁺); IR (KBr thinfilm) 3055, 2971, 2773, 1656 cm⁻¹.

Example 173 Preparation ofN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-2-(2-methoxyethoxy)acetamide(Compound Y2195)

To a stirred solution of 2-methoxyethanol (0.07 mL, 0.87 mmol) in THF (4mL) at 0° C. was added sodium hydride (0.032 g, 0.80 mmol, 60%dispersion in oil). After stirring for 10 min2-chloro-N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethylacetamide(0.2 g, 0.7 mmol) was added in one portion. The reaction was stirred for20 minutes then the reaction vessel was removed from the ice bath andallowed to warm to room temperature and was stirred overnight (ca 16 h),at which point the reaction was deemed complete by TLC. The reactionmixture was diluted with water and ethyl acetate and the layers wereseparated. The aqueous layer was extracted with ethyl acetate once. Thecombined organic layers were dried over MgSO₄, concentrated underreduced pressure, and purified by flash chromatography (SiO₂, 100-200mesh; eluting with 0 to 20% methanol in CH₂Cl₂) to afford the titlecompound as a tan solid (0.045 g, 20%).

Example 174 Preparation ofN-((3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)(methyl)carbamoyl)-N-ethylpivalamide(Compound Y2082)

To a solution of1-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-3-ethyl-1-methylurea(0.075 g, 0.268 mmol) in THF (2.68 mL) at −78° C. was added 1 M lithiumbis(trimethylsilyl)amide (LiHMDS) (0.282 mL, 0.282 mmol) in toluene. Thereaction was stirred at −78° C. for 15 min and pivaloyl chloride (0.036mL, 0.295 mmol) was added and the reaction was stirred at −78° C. for 10min and room temperature for 30 min. Brine was added and the reactionwas extracted with EtOAc. The combined organic phases were concentratedand purified by flash chromatography (0-15% MeOH/CH₂Cl₂) to give thetitle compound as a yellow oil (54 mg, 55%): IR (thin film) 2969, 1681cm⁻¹; H NMR (400 MHz, CDCl₃) δ 8.93 (d, J=2.5 Hz, 1H), 8.61 (dd, J=4.7,1.3 Hz, 1H), 8.06 (s, 1H), 8.00 (ddd, J=8.3, 2.6, 1.4 Hz, 1H), 7.44 (dd,J=8.3, 4.7 Hz, 1H), 3.58 (q, J=7.0 Hz, 2H), 3.35 (s, 3H), 1.25-1.13 (m,12H); ESIMS m/z 365 ([M+H]⁺).

Example 175 Preparation ofN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-3-(methylthio)propanimidamide(Compound 706)

To a solution of 3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-amine (0.058 g,0.297 mmol) in EtOH (0.992 mL) was added naphthalen-2-ylmethyl3-(methylthio)propanimidothioate hydrobromide (0.106 g, 0.297 mmol). Thereaction was stirred at 0° C. for 1 hour. The solvent was removed underreduced pressure and water and Et₂O were added. The phases wereseparated and the aqueous phase was concentrated to give a crudemixture. The residue was dissolved in MeOH (1 mL) and MP-carbonate(0.281 g, 0.892 mmol) was added. The reaction was stirred at roomtemperature for 1 hour. The reaction was filtered, concentrated andpurified by flash chromatography (0-15% MeOH/hexanes) to give the titlecompound as light brown solid (32 mg, 31%): mp 137° C.; ¹H NMR (300 MHz,CDCl₃) δ 8.86 (d, J=2.6 Hz, 1H), 8.49 (dd, J=4.8, 1.2 Hz, 1H), 7.95(ddd, J=8.3, 2.5, 1.3 Hz, 1H), 7.68 (s, 1H), 7.37 (dd, J=8.3, 4.8 Hz,1H), 5.29 (br s, 2H), 3.02-2.73 (m, 2H), 2.64 (t, J=7.1 Hz, 2H), 2.18(s, 3H); ESIMS m/z 297 ([M+H]⁺).

Example 176 Preparation of naphthalen-2-ylmethyl3-(methylthio)propanimidothioate hydrobromide

To a solution of 3-(methylthio)propanethioamide (0.062 g, 0.458 mmol) inCHCl₃ (1.146 mL) was added 2-(bromomethyl)naphthalene (0.101 g, 0.458mmol). The mixture was heated at reflux for 1.5 hours. The reaction wascooled to room temperature, Et₂O was added and a precipitate formed. Thesolvent was removed under reduced pressure. Et₂O was added andsubsequently decanted. The residual solid was dried under reducedpressure to give the title compound as a faint yellow solid (109 mg,67%): ¹H NMR (300 MHz, DMSO-d₆) δ 11.78 (br s, 1H), 8.00 (s, 1H),7.98-7.85 (m, 3H), 7.59-7.49 (m, 3H), 4.74 (s, 2H), 3.10 (t, J=7.1 Hz,2H), 2.84 (t, J=7.2 Hz, 2H), 2.08 (s, 3H). Reference: Shearer, B. G. etal. Tetrahedron Letters 1997, 38, 179-182.

Naphthalen-2-ylmethyl N-methyl-3-(methylthio)propanimidothioatehydrobromide was prepared in accordance with the procedure disclosed inExample 176 and isolated as an off-white semi-solid; ¹H NMR (400 MHz,DMSO-d₆) δ 8.08 (s, 1H), 8.02-7.93 (m, 3H), 7.63-7.56 (m, 3H), 5.02 (s,2H), 3.40-3.32 (m, 2H), 3.21 (s, 3H), 2.89-2.83 (m, 2H), 2.13 (s, 3H);ESIMS m/z 290 ([M+H]⁺).

Naphthalen-2-ylmethyl N-methylethanimidothioate hydrobromide wasprepared in accordance with the procedure disclosed in Example 176 andisolated as a white solid; ¹H NMR (400 MHz, DMSO-d₆) δ 8.02 (s, 1H),8.01-7.92 (m, 3H), 7.61-7.53 (m, 3H), 4.93 (s, 2H), 3.15 (d, J=1.1 Hz,3H), 2.81 (d, J=1.1 Hz, 3H); ESIMS m/z 230 ([M+H]⁺).

Naphthalen-2-ylmethyl ethanimidothioate hydrobromide was prepared asdescribed in Shearer, B. G. et al. Tetrahedron Letters 1997, 38,179-182.

Naphthalen-2-ylmethyl cyclopropanecarbimidothioate hydrobromide wasprepared in accordance with the procedure disclosed in Example 176 andisolated as a yellow solid; ¹H NMR (400 MHz, DMSO-d₆) δ 11.58 (s, 1H),8.01 (s, 1H), 7.99-7.88 (m, 3H), 7.59-7.51 (m, 3H), 4.77 (s, 2H),2.42-2.29 (m, 1H), 1.46-1.37 (m, 2H), 1.36-1.29 (m, 2H); ESIMS m/z 242([M+H]⁺).

Example 177 Preparation of ethylN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N′-ethyl-N-methylcarbamimidothioate(Compound Y2049)

To a solution of1-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-3-ethyl-1-methylthiourea(0.085 g, 0.287 mmol) in ethanol (1.916 mL) in a microwave vial wasadded iodoethane (0.028 mL, 0.345 mmol). The reaction was heated in amicrowave (CEM Discover®) with external IR-sensor temperature monitoringfrom the bottom of the vessel at 80° C. for 6 hours. The reaction wasconcentrated and purified by flash chromatography (0-100% EtOAc/Hexanes)to give the title compound as a yellow oil (56 mg, 57%): IR (thin film)3050, 2931, 1583 cm⁻¹; H NMR (300 MHz, CDCl₃) δ 9.05 (d, J=2.6 Hz, 1H),8.91 (s, 1H), 8.59-8.48 (m, 1H), 8.13-8.04 (m, 1H), 7.40 (dd, J=8.4, 4.8Hz, 1H), 3.81 (q, J=7.2 Hz, 2H), 3.73 (s, 3H), 2.95 (q, J=14.1, 7.0 Hz,2H), 1.44-1.28 (m, 6H); ESIMS m/z 325 ([M+H]⁺).

Example 178 Preparation ofN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-3-(N-methyl-N-(3,3,3-trifluoropropyl)sulfamoyl)propanamide(Compound 965)

To a stirred solution ofN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-3-mercaptopropanamide(200 mg, 0.64 mmol), tetrabutylammonium chloride (715 mg, 2.57 mmol) andwater (29 mg, 1.61 mmol) in acetonitrile (30 mL) at 0° C. was added1-chloropyrrolidine-2,5-dione (258 mg, 1.93 mmol) in portions over 3min. After stirring for 1 hour, 3,3,3-trifluoro-N-methylpropan-1-amine(82 mg, 0.64 mmol) was added and the reaction was stirred for additional14 hours at room temperature. The mixture was filtered and concentratedin vacuo to give a brown residue. Purification of this residue on silicagel eluting with CH₂Cl₂ and methanol afforded the title compound as anoff-white gum (71 mg, 22%).

Example 179 Preparation ofN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-3-((1-chloro-2,2,2-trifluoroethyl)thio)-N-ethylpropanamide(Compound 859)

To a suspension ofN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-3-mercaptopropanamide(0.100 g, 0.322 mmol), sodium dithionite (0.070 g, 0.338 mmol) andsodium bicarbonate (0.028 g, 0.338 mmol) in DMSO (3.22 mL) at 40° C. wasadded 2-bromo-2-chloro-1,1,1-trifluoroethane (0.079 g, 0.402 mmol)dropwise. The reaction was stirred at the same temperature for 3 h afterwhich the reaction was cooled, poured into water (10 mL) and extractedwith EtOAc (3×20 mL). The combined organic extracts were washed withwater (2×50 mL) and half-saturated brine (3×50 mL) and then dried overNa₂SO₄, filtered and concentrated in vacuo. The crude residue waspurified via normal phase flash chromatography (0 to 100% EtOAc/CH₂Cl₂)to afford the desired product as a clear, viscous oil (111 mg, 77%).(Reference: Pustovit, et al., Synthesis, 2010, 7, 1159-1165).

Example 180 Preparation ofN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-3-((3-(mesitylamino)-3-oxopropyl)thio)propanamide(Compound 1024)

To a stirred solution ofN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-3-mercaptopropanamide(0.20 g, 0.64 mmol) in acetonitrile (2.1 mL) was added3-bromo-N-mesitylpropanamide (0.17 g, 0.64 mmol) and cesium carbonate(0.23 g, 0.70 mmol) and the reaction was stirred overnight at roomtemperature. The reaction was loaded directly onto celite and placed ina vacuum oven overnight at 25° C. The crude product was purified bysilica gel chromatography eluting with 0-75% ethyl acetate/hexanes togive the desired product as a white semi-solid (226 mg, 53%).

Example 181 Preparation of two enantiomers ofN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-3-((3,3,3-trifluoropropyl)sulfinyl)propanamide(Compounds 1028

The two enantiomers of the title molecule were separated by chiral HPLCusing a RegisCell™ semi-preparative column (25 cm×10.0 mm, 5 micron)using 0.1% TFA in hexane and isopropanol as the mobile phase (15 to 30%gradient IPA/hexane in 15 minutes, then hold to 20 minutes) with a flowrate of 15 mL/min at ambient temperature. Under these conditionscompound 1028 was collected at a retention time of 6.0 min and possessedan optical rotation of [α]_(D) ³⁰=+25.9 (c 0.27% in CDCl₃). Compound1029 was collected at a retention time of 7.5 min and possessed anoptical rotation of [α]_(D) ³⁰=−27.4 (c 0.27% in CDCl₃).Characterization data for these molecules are listed in Table 2.

Example 182 Preparation ofN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-4,4,4-trifluoro-N-methyl-3-(methylsulfonyl)butanamide(Compound 714)

To a 20 mL vial was addedN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-4,4,4-trifluoro-N-methyl-3-(methylsulfinyl)butanamide(130 mg, 0.329 mmol) and DCM (3 mL). m-CPBA (83 mg, 0.362 mmol) wasadded and the solution was stirred at room temperature for 3 hours. Thereaction was quenched by the addition of sodium sulfite solution,extracted with DCM and concentrated. Purification with silica gelchromatography (0-100% EtOAc/hexane) affordedN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-4,4,4-trifluoro-N-methyl-3-(methylsulfonyl)butanamideas a white solid (25 mg, 18%).

Example 183 Preparation of enantiomers ofN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-2-methyl-3-(methylsulfinyl)propanamide(Compounds 804-807)

The four stereoisomers of the title compound were separated by chiralHPLC using Chiralpak IC column (30×250 mm) using 0.2% TFA and 0.2%isopropylamine in hexane and isopropanol as the mobile phase (25% IPA inhexane) at ambient temperature. Under these conditions compound 804 wascollected at a retention time of 8.4 minutes and possessed an opticalrotation of [α]_(D) ³⁰=−43.8 (c 0.5% in CDCl₃). Compound 805 wascollected at a retention time of 11.9 minutes and possessed an opticalrotation of [α]_(D) ³⁰=+48.2 (c 0.5% in CDCl₃). Compound 806 wascollected at a retention time of 16.4 minutes and possessed an opticalrotation of [α]_(D) ³⁰=+113.4 (c 0.5% in CDCl₃). Compound 807 wascollected at a retention time of 20.6 minutes and possessed an opticalrotation of [α]_(D) ³⁰=−93.0 (c 0.5% in CDCl₃). Characterization datafor these molecules are listed in Table 2.

Example 184 Preparation of 3-((3,3,3-trifluoropropyl)thio)propanoylchloride

A dry 5 L round bottom flask equipped with magnetic stirrer, nitrogeninlet, reflux condenser, and thermometer, was charged with3-((3,3,3-trifluoropropyl)thio)propanoic acid (188 g, 883 mmol) indichloromethane (3 L). Thionyl chloride (525 g, 321 mL, 4.42 mol) wasthen added dropwise over 50 minutes. The reaction mixture was heated toreflux (36° C.) for two hours, then cooled to ambient temperature.Concentration under vacuum on a rotary evaporator, followed bydistillation (40 Torr, product collected from 123-127° C.) gave thetitle compound as a clear colorless liquid (177.3 g, 86%): ¹H NMR (400MHz, CDCl₃) δ 3.20 (t, J=7.1 Hz, 2H), 2.86 (t, J=7.1 Hz, 2H), 2.78-2.67(m, 2H), 2.48-2.31 (m, 2H); ¹⁹F NMR (376 MHz, CDCl₃) δ-66.42, −66.43,−66.44, −66.44.

Example 185 Preparation of3-chloro-1-(5-chloropyridin-3-yl)-1H-pyrazol-4-amine

To a solution of tert-butyl(3-chloro-1H-pyrazol-4-yl) carbamate (5 g,22.97 mmol) in a mixture of DMF-H₂O (9:1) (40 mL) was added copperiodide (0.13 g, 0.69 mmol, 0.03 eq), cesium carbonate (14.97 g, 45.9mmol), 8-hydroxy quinoline (0.33 g, 2.30 mmol) and3-bromo-5-chloropyridine (5.29 g, 27.5 mmol). The mixture was heated at140° C. under nitrogen for 11 hours. The reaction mixture was cooled toroom temperature, quenched with ammonium hydroxide (15 mL), filteredthrough celite and the filtrate was extracted with ethyl acetate (3×50mL). The combined organic layer was washed with brine (1×50 mL) driedover anhydrous Na₂SO₄, filtered, and evaporated to dryness under reducedpressure. The crude product was purified on silica gel using 0-100%ethyl acetate in hexane as eluent to give the title compound as darkbrown amorphous solid (1.35 g, 26%): ¹H NMR (400 MHz, DMSO-d₆) δ 8.93(d, J=2.24 Hz, 1H), 8.48 (d, J=2.00 Hz, 1H), 8.25 (t, J=2.16 Hz, 1H),7.96 (s, 1H), 4.52 (bs, 2H); ESIMS m/z 231 ([M+2H]⁺).

The following molecules were made in accordance with the proceduresdisclosed in Example 185:

1-(5-Bromopyridin-3-yl)-3-chloro-1H-pyrazol-4-amine: ESIMS m/z 274([M+H]⁺).

3-Chloro-1-(5-methoxypyridin-3-yl)-1H-pyrazol-4-amine: ESIMS m/z 225([M+H]⁺).

3-Chloro-1-(5-methylpyridin-3-yl)-1H-pyrazol-4-amine: ¹H NMR (400 MHz,DMSO-d₆, D₂O): δ 8.68 (s, 1H), 8.27 (s, 1H), 7.86 (d, J=5.64 Hz, 2H),2.34 (s, 3H); ESIMS m/z 209 ([M+H]⁺).

Example 186 Preparation oftert-butyl(3-chloro-1-(5-chloropyridin-3-yl)-1H-pyrazol-4-yl)carbamate

To a solution of amine3-chloro-1-(5-chloropyridin-3-yl)-1H-pyrazol-4-amine (1.00 g, 4.4 mmol)and triethylamine (666 mg, 6.6 mmol) in dry THF (10 mL) was addeddi-tert-butyl dicarbonate anhydride (960 mg, 4.62 mmol) over 30 minutesand the reaction was allowed to stir at room temperature for 18 hours.The reaction was diluted with water (10 mL) and extracted with ethylacetate (50 mL×2). The organic phase was washed with brine (10 mL),dried over Na₂SO₄, and concentrated under reduced pressure. Purificationby silica gel column chromatography using hexanes as an eluent affordedthe titled compound (651 mg, 46%): ESIMS m/z 330 ([M+H]⁺).

The following molecules were made in accordance with the proceduresdisclosed in Example 186:

tert-Butyl(1-(5-bromopyridin-3-yl)-3-chloro-1H-pyrazol-4-yl)carbamate:ESIMS m/z 372 ([M+H]⁺).

tert-Butyl(3-chloro-1-(5-methylpyridin-3-yl)-1H-pyrazol-4-yl)carbamate:ESIMS m/z 309 ([M+H]⁺).

Example 187 Preparation oftert-butyl(3-chloro-1-(5-chloropyridin-3-yl)-1H-pyrazol-4-yl)(methyl)carbamate

To a solution oftert-butyl(3-chloro-1-(5-chloropyridin-3-yl)-1H-pyrazol-4-yl)carbamate(501 mg, 1.5 mmol) in dry THF (10 mL) was added potassium tert-butoxide(1.5 mL, 1 M solution in THF) and the reaction was stirred for 30 min.Methyl iodide (317 mg, 2.25 mmol) was added slowly at 0° C. and stirredfor an additional 18 hours at room temperature. The mixture was quenchedwith saturated aqueous ammonium chloride and extracted with ethylacetate (2×20 mL). The combined organic extract was washed with brinesolution (1×20 mL), dried over Na₂SO₄ and evaporated to dryness underreduced pressure. The crude product was purified on silica gel usinghexanes and ethyl acetate as eluent (0-10%) to give the title compound(220 mg, 42%): ESIMS m/z 345 ([M+H]⁺).

The following molecules were made in accordance with the proceduresdisclosed in Example 187:

tert-Butyl(1-(5-bromopyridin-3-yl)-3-chloro-1H-pyrazol-4-yl)(methyl)carbamate:ESIMS m/z 387 ([M+H]⁺).

tert-Butyl(3-chloro-1-(5-methylpyridin-3-yl)-1H-pyrazol-4-yl)(methyl)carbamate:ESIMS m/z 265 ([M−t−Bu]⁺).

Example 188 Preparation of3-chloro-1-(5-chloropyridin-3-yl)-N-methyl-1H-pyrazol-4-amine

tert-Butyl(3-chloro-1-(5-chloropyridin-3-yl)-1H-pyrazol-4-yl)(methyl)carbamate(343 mg, 1 mmol, 1.0 eq) was dissolved in 1,4-dioxane (10 mL) and thesolution was cooled to 0° C. A solution of HCl in dioxane (5 mL, 4 M)was added dropwise, and the mixture was stirred for 2 hours, thenconcentrated under reduced pressure. The residue was diluted with CH₂Cl₂(50 mL), and the solution washed with aqueous sodium bicarbonate, water(10 mL) and brine (10 mL). The organic layer was dried over Na₂SO₄, andconcentrated under reduced pressure to give the title compound (148 mg,61%): ESMS m/z 244 ([M+H]⁺).

The following molecule was made in accordance with the proceduresdisclosed in Example 188:

1-(5-Bromopyridin-3-yl)-3-chloro-N-methyl-1H-pyrazol-4-amine: ESIMS m/z289 ([M+H]⁺).

Example 189 Preparation ofN-(3-chloro-1-(5-methoxypyridin-3-yl)-1H-pyrazol-4-yl)-2,2,2-trifluoroacetamide

To a solution of 3-chloro-1-(5-methoxypyridin-3-yl)-1H-pyrazol-4-amine(1.0 g, 4.46 mmol) and pyridine (530 mg, 6.69 mmol) in drydichloromethane (10 mL) was added trifluoroacetic anhydride (1.0 eq)dropwise at 0° C. The reaction mixture was slowly warmed to roomtemperature and stirred for 4 hours. The reaction mixture was dilutedwith water (10 mL) and extracted with ethyl acetate (2×50 mL). Theorganic phase was washed with brine (10 mL), dried over Na₂SO₄ andconcentrated under reduced pressure. The crude product was purified oversilica eluting with hexanes and ethyl acetate to afford the titlecompound (700 mg, 49%): ESIMS m/z 321 ([M+H]⁺).

Example 190 Preparation ofN-(3-chloro-1-(5-methoxypyridin-3-yl)-1H-pyrazol-4-yl)-2,2,2-trifluoro-N-methylacetamide

To a solution ofN-(3-chloro-1-(5-methoxypyridin-3-yl)-1H-pyrazol-4-yl)-2,2,2-trifluoroacetamide(700 mg, 2.18 mmol) in dry THF (10 mL) was added potassium tert-butoxide(1 M solution in THF, 0.32 mL, 3.2 mmol) at 0° C. and the reaction wasstirred for 30 min. Methyl iodide (466 mg, 3.28 mmol) was added slowlyat 0° C. and the reaction was stirred for an additional 18 hours at roomtemperature. The reaction was quenched with saturated ammonium chloridesolution and extracted with ethyl acetate (2×20 mL). The combinedorganic extract was washed with brine (1×20 mL), dried over Na₂SO₄ andevaporated to dryness under reduced pressure. The crude product waspurified on silica eluting with hexanes and ethyl acetate (0-30%) togive the title compound (426 mg, 58% yield): ESIMS m/z 335 ([M+H]⁺).

Example 191 Preparation of3-chloro-1-(5-methoxypyridin-3-yl)-N-methyl-1H-pyrazol-4-amine

To a suspension ofN-(3-chloro-1-(5-methoxypyridin-3-yl)-1H-pyrazol-4-yl)-2,2,2-trifluoro-N-methylacetamide(410 mg, 1.23 mmol) in methanol (10 mL) was added K₂CO₃ (254 mg, 1.8mmol) and the mixture stirred at room temperature for 4 hours. Thereaction was concentrated under reduced pressure and the residuesuspended in dichloromethane (50 mL), and washed with water (10 mL) andbrine (10 mL). The organic layer was dried over Na₂SO₄, and concentratedunder reduced pressure to give the title compound (206 mg, 71%): ESIMSm/z 239 ([M+H]⁺).

Example 192 Preparation ofdiethyl(2-((3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)(ethyl)amino)-2-oxoethyl)phosphonate

To a solution of 3-chloro-N-ethyl-1-(pyridin-3-yl)-1H-pyrazol-4-amine(2.00 g, 8.98 mmol), 2-(diethoxyphosphoryl)acetic acid (1.94 mg, 9.88mmol) and N,N-dimethylpyridin-4-amine (2.20 g, 17.96 mmol) in dry DMF(10 mL) was addedN′-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diaminehydrochloride (2.58 g, 13.47 mmol), and the mixture was stirred at 0° C.for 2 hours. The mixture was diluted with water and extracted with ethylacetate (75 mL×2). The combined organic extract was washed withsaturated aqueous NH₄Cl, sat aqueous NaHCO₃ and brine, dried over MgSO₄,filtered and concentrated in vacuo to give a brown residue. This residuewas purified on silica gel eluting with CH₂Cl₂ and methanol to give thetitle compound as a brown solid (2.62 g, 69%): mp 46-48° C.; ¹H NMR (400MHz, CDCl₃) δ 9.00 (dd, J=2.7, 0.7 Hz, 1H), 8.62 (dd, J=4.7, 1.4 Hz,1H), 8.35 (s, 1H), 8.03 (ddd, J=8.3, 2.7, 1.5 Hz, 1H), 7.44 (ddd, J=8.3,4.8, 0.8 Hz, 1H), 4.28-4.02 (m, 4H), 3.79 (m, 2H), 2.89 (d, J=22.0 Hz,2H), 1.40-1.22 (m, 6H), 1.17 (t, J=7.2 Hz, 3H); ESIMS m/z 401[(M+H)⁺]399 [(M−H)⁻].

Example 193 Preparation of(E)-N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-5,5,5-trifluoropent-2-enamide(Compound Y2177)

To a solution ofdiethyl(2-((3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)(ethyl)amino)-2-oxoethyl)phosphonate(500 mg, 1.25 mmol) in THF (4 mL) was added sodium hydride (55 mg, 1.37mmol, 60% wt. oil suspension) and the mixture stirred at 0° C. for 20min. The mixture was cooled to −78° C. and 3,3,3-trifluoropropanal (210mg, 1.87 mmol) was added and the reaction was stirred for 1 hour. Themixture was then warmed to room temperature and stirred at roomtemperature for 2 hours. Additional NaH (30 mg, 0.75 mmol, 60% wt. oilsuspension) was added and the mixture stirred at room temperature for0.5 h. The mixture was diluted with water and ethyl acetate and theorganic phase separated, washed with brine, dried over MgSO₄ andconcentrated in vacuo to give a brown oily residue. This residue waspurified on silica gel eluting with CH₂Cl₂ and methanol to give thetitle compound as a light yellow gum (230 mg, 51%).

Example 194 Preparation ofN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-3-((3,3-difluoroallyl)thio)-N-ethylpropanamide(Compound 918)

To a solution of3-((3-bromo-3,3-difluoropropyl)thio)-N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethylpropanamide(100 mg, 0.21 mmol) in dioxane (1 mL) was added2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (32 mg, 0.21 mmol) andthe mixture stirred at 120° C. for 30 min in a Biotage® Initiatormicrowave reactor with external IR-sensor temperature monitoring fromthe side of the vessel. The mixture was diluted with ethyl acetate andthen washed with saturated aqueous ammonium chloride and brine, driedover MgSO₄ and concentrated in vacuo to give a brown gum. This gum waspurified on silica gel eluting with methylene chloride and methanol togive the title compound as a light yellow oil (76 mg, 92%).

Example 195 Preparation of1-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-3-ethyl-1,3-dimethylurea(Compound Y2012)

To a solution of 3-chloro-N-methyl-1-(pyridin-3-yl)-1H-pyrazol-4-amine(0.100 g, 0.48 mmol) in CH₂Cl₂ (1.9 ml) was addedN-ethyl-N-isopropylpropan-2-amine (0.21 ml, 1.20 mmol) followed byethyl(methyl)carbamic chloride (0.117 g, 0.959 mmol) and the reactionmixture was stirred at ambient temperature for 2 hours. The reaction wasquenched by the addition of saturated sodium bicarbonate. The aqueouslayer was extracted with CH₂Cl₂. The combined organic layers were driedover sodium sulfate, filtered, concentrated in vacuo and purified viasilica gel column chromatography (0-100% ethyl acetate/hexanes) toafford the title compound as a yellow oil (57 mg, 36%).

Example 196 Preparation ofN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-2-(2,2,2-trifluoroethoxy)propanamide(Compound Y2001)

To a solution of 2,2,2-trifluoroethanol (128 mg, 1.3 mmol) in DMF (1.3mL) was added sodium hydride (51.1 mg, 1.3 mmol). The reaction mixturewas stirred for 30 min until the mixture became clear and no H₂evolution was observed. To this solution was added2-chloro-N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethylpropanamide(200 mg, 0.64 mmol) and the reaction mixture was stirred at 50° C.overnight. The reaction mixture was diluted with CH₂Cl₂ and washed withwater, the phases were separated with a Biotage® Phase separator andthen concentrated. The residue was purified by silica gel chromatographyeluting with 0-50% acetone in hexanes to afford the titled compound as awhite solid (156 mg, 64%).

Example 197 Preparation ofN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-2-((methylthio)methoxy)propanamide(Compound Y2199)

To a solution ofN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-2-hydroxypropanamide(100 mg, 0.34 mmol) in THF (1.1 mL) was added sodium hydride (60% inmineral oil, 33.9 mg, 0.85 mmol). The mixture was stirred for 15 min andthen (chloromethyl)(methyl)sulfane (33.6 μL, 0.41 mmol) was added. Afterstirring at ambient temp overnight the reaction mixture was diluted withCH₂Cl₂ and washed with water. The phases were separated and dried with aBiotage® Phases Separator© and concentrated in vacuo. The residue waspurified by silica chromatography eluting with 0-70% acetone in hexanesto afford the titled compound as an off white solid (73 mg, 63%).

Example 198 Preparation ofN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-2,2-difluoro-N-methyl-2-(methylthio)acetamide(Compound Y2021)

To a solution of2-bromo-N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-2,2-difluoro-N-methylacetamide(250 mg, 0.684 mmol) in DMSO (2.3 mL) was added methanethiol, sodiumsalt (96 mg, 1.37 mmol). The reaction mixture was heated to 50° C. for 3h and then diluted with water and extracted with CH₂Cl₂. The organicphases were dried with MgSO₄, filtered and concentrated in vacuo. Theresidue was purified by silica gel chromatography eluting with 0-80%acetone in hexanes to afford the titled compound as a red oil (188 mg,83%).

Example 199 Preparation of3-chloro-N-ethyl-1-(pyridin-3-yl)-1H-pyrazol-4-amine

To a 100 mL round bottom flask charged with3-chloro-N-ethyl-1-(pyridin-3-yl)-1H-pyrazol-4-amine-bis HCl salt (2 g,6.77 mmol) was added DCM (20 mL) and the suspension was stirred at roomtemperature. To this suspension was added saturated NaHCO₃ solutionslowly until the bubbling stopped and the aqueous layer became basic.The mixture was loaded into a separatory funnel, the organic layer wasseparated and the aqueous layer was extracted with DCM (2×10 mL). Thecombined DCM layers were dried and concentrated to give the titlecompound as an off-white solid (1.41 g, 94%). Analytical data of3-chloro-N-ethyl-1-(pyridin-3-yl)-1H-pyrazol-4-amine can be found inExample 8.

Example A Bioassays on Green Peach APHID (“GPA”) (Myzus persicae)(MYZUPE)

GPA is the most significant aphid pest of peach trees, causing decreasedgrowth, shriveling of the leaves, and the death of various tissues. Itis also hazardous because it acts as a vector for the transport of plantviruses, such as potato virus Y and potato leafroll virus to members ofthe nightshade/potato family Solanaceae, and various mosaic viruses tomany other food crops. GPA attacks such plants as broccoli, burdock,cabbage, carrot, cauliflower, daikon, eggplant, green beans, lettuce,macadamia, papaya, peppers, sweet potatoes, tomatoes, watercress, andzucchini, among other plants. GPA also attacks many ornamental cropssuch as carnation, chrysanthemum, flowering white cabbage, poinsettia,and roses. GPA has developed resistance to many pesticides.

Certain molecules disclosed in this document were tested against GPAusing procedures described in the following example. In the reporting ofthe results, “Table 3: GPA (MYZUPE) and sweetpotato whitefly-crawler(BEMITA) Rating Table” was used (See Table Section).

Cabbage seedlings grown in 3-inch pots, with 2-3 small (3-5 cm) trueleaves, were used as test substrate. The seedlings were infested with20-50 GPA (wingless adult and nymph stages) one day prior to chemicalapplication. Four pots with individual seedlings were used for eachtreatment. Test compounds (2 mg) were dissolved in 2 mL ofacetone/methanol (1:1) solvent, forming stock solutions of 1000 ppm testcompound. The stock solutions were diluted 5× with 0.025% Tween 20 inH₂O to obtain the solution at 200 ppm test compound. A hand-heldaspirator-type sprayer was used for spraying a solution to both sides ofcabbage leaves until runoff. Reference plants (solvent check) weresprayed with the diluent only containing 20% by volume ofacetone/methanol (1:1) solvent. Treated plants were held in a holdingroom for three days at approximately 25° C. and ambient relativehumidity (RH) prior to grading. Evaluation was conducted by counting thenumber of live aphids per plant under a microscope. Percent Control wasmeasured by using Abbott's correction formula (W. S. Abbott, “A Methodof Computing the Effectiveness of an Insecticide” J. Econ. Entomol. 18(1925), pp. 265-267) as follows.

Corrected % Control=100*(X−Y)/X

-   -   where    -   X=No. of live aphids on solvent check plants and    -   Y=No. of live aphids on treated plants

The results are indicated in the table entitled “Table 4. BiologicalData for GPA (MYZUPE) and sweetpotato whitefly-crawler (BEMITA)” (SeeTable Section).

Example B Insecticidal Test for Sweetpotato Whitefly-Crawler (Bemisiatabaci) (BEMITA) in Foliar Spray Assay

Cotton plants grown in 3-inch pots, with 1 small (3-5 cm) true leaf,were used as test substrate. The plants were placed in a room withwhitefly adults. Adults were allowed to deposit eggs for 2-3 days. Aftera 2-3 day egg-laying period, plants were taken from the adult whiteflyroom. Adults were blown off leaves using a hand-held Devilbiss sprayer(23 psi). Plants with egg infestation (100-300 eggs per plant) wereplaced in a holding room for 5-6 days at 82° F. and 50% RH for egg hatchand crawler stage to develop. Four cotton plants were used for eachtreatment. Compounds (2 mg) were dissolved in 1 mL of acetone solvent,forming stock solutions of 2000 ppm. The stock solutions were diluted10× with 0.025% Tween 20 in H₂O to obtain a test solution at 200 ppm. Ahand-held Devilbiss sprayer was used for spraying a solution to bothsides of cotton leaf until runoff. Reference plants (solvent check) weresprayed with the diluent only. Treated plants were held in a holdingroom for 8-9 days at approximately 82° F. and 50% RH prior to grading.Evaluation was conducted by counting the number of live nymphs per plantunder a microscope. Insecticidal activity was measured by using Abbott'scorrection formula and presented in “Table 4. Biological Data for GPA(MYZUPE) and sweetpotato whitefly-crawler (BEMITA)” (see column“BEMITA”):

Corrected % Control=100*(X−Y)/X

where X=No. of live nymphs on solvent check plants

-   -   Y=No. of live nymphs on treated plants

Pesticidally Acceptable Acid Addition Salts, Salt Derivatives, Solvates,Ester Derivatives, Polymorphs, Isotopes and Radionuclides

Molecules of Formula One may be formulated into pesticidally acceptableacid addition salts. By way of a non-limiting example, an amine functioncan form salts with hydrochloric, hydrobromic, sulfuric, phosphoric,acetic, benzoic, citric, malonic, salicylic, malic, fumaric, oxalic,succinic, tartaric, lactic, gluconic, ascorbic, maleic, aspartic,benzenesulfonic, methanesulfonic, ethanesulfonic,hydroxymethanesulfonic, and hydroxyethanesulfonic acids. Additionally,by way of a non-limiting example, an acid function can form saltsincluding those derived from alkali or alkaline earth metals and thosederived from ammonia and amines. Examples of preferred cations includesodium, potassium, and magnesium.

Molecules of Formula One may be formulated into salt derivatives. By wayof a non-limiting example, a salt derivative can be prepared bycontacting a free base with a sufficient amount of the desired acid toproduce a salt. A free base may be regenerated by treating the salt witha suitable dilute aqueous base solution such as dilute aqueous sodiumhydroxide (NaOH), potassium carbonate, ammonia, and sodium bicarbonate.As an example, in many cases, a pesticide, such as 2,4-D, is made morewater-soluble by converting it to its dimethylamine salt.

Molecules of Formula One may be formulated into stable complexes with asolvent, such that the complex remains intact after the non-complexedsolvent is removed. These complexes are often referred to as “solvates.”However, it is particularly desirable to form stable hydrates with wateras the solvent.

Molecules of Formula One may be made into ester derivatives. These esterderivatives can then be applied in the same manner as the inventiondisclosed in this document is applied.

Molecules of Formula One may be made as various crystal polymorphs.Polymorphism is important in the development of agrochemicals sincedifferent crystal polymorphs or structures of the same molecule can havevastly different physical properties and biological performances.

Molecules of Formula One may be made with different isotopes. Ofparticular importance are molecules having ²H (also known as deuterium)in place of ¹H.

Molecules of Formula One may be made with different radionuclides. Ofparticular importance are molecules having ¹³C or ¹⁴C.

Stereoisomers

Molecules of Formula One may exist as one or more stereoisomers. Thus,certain molecules can be produced as racemic mixtures. It will beappreciated by those skilled in the art that one stereoisomer may bemore active than the other stereoisomers. Individual stereoisomers maybe obtained by known selective synthetic procedures, by conventionalsynthetic procedures using resolved starting materials, or byconventional resolution procedures. Certain molecules disclosed in thisdocument can exist as two or more isomers. The various isomers includegeometric isomers, diastereomers, and enantiomers. Thus, the moleculesdisclosed in this document include geometric isomers, racemic mixtures,individual stereoisomers, and optically active mixtures. It will beappreciated by those skilled in the art that one isomer may be moreactive than the others. The structures disclosed in the presentdisclosure are drawn in only one geometric form for clarity, but areintended to represent all geometric forms of the molecule.

Combinations

Molecules of Formula One may also be used in combination (such as, in acompositional mixture, or a simultaneous or sequential application) withone or more compounds having acaricidal, algicidal, avicidal,bactericidal, fungicidal, herbicidal, insecticidal, molluscicidal,nematicidal, rodenticidal, or virucidal properties. Additionally, themolecules of Formula One may also be used in combination (such as, in acompositional mixture, or a simultaneous or sequential application) withcompounds that are antifeedants, bird repellents, chemosterilants,herbicide safeners, insect attractants, insect repellents, mammalrepellents, mating disrupters, plant activators, plant growthregulators, or synergists.

Examples of such compounds in the above groups that may be used with theMolecules of Formula One are—(3-ethoxypropyl)mercury bromide,1,2-dichloropropane, 1,3-dichloropropene, 1-methylcyclopropene,1-naphthol, 2-(octylthio)ethanol, 2,3,5-tri-iodobenzoic acid, 2,3,6-TBA,2,3,6-TBA-dimethylammonium, 2,3,6-TBA-lithium, 2,3,6-TBA-potassium,2,3,6-TBA-sodium, 2,4,5-T, 2,4,5-T-2-butoxypropyl, 2,4,5-T-2-ethylhexyl,2,4,5-T-3-butoxypropyl, 2,4,5-TB, 2,4,5-T-butometyl, 2,4,5-T-butotyl,2,4,5-T-butyl, 2,4,5-T-isobutyl, 2,4,5-T-isoctyl, 2,4,5-T-isopropyl,2,4,5-T-methyl, 2,4,5-T-pentyl, 2,4,5-T-sodium,2,4,5-T-triethylammonium, 2,4,5-T-trolamine, 2,4-D,2,4-D-2-butoxypropyl, 2,4-D-2-ethylhexyl, 2,4-D-3-butoxypropyl,2,4-D-ammonium, 2,4-DB, 2,4-DB-butyl, 2,4-DB-dimethylammonium,2,4-DB-isoctyl, 2,4-DB-potassium, 2,4-DB-sodium, 2,4-D-butotyl,2,4-D-butyl, 2,4-D-diethylammonium, 2,4-D-dimethylammonium,2,4-D-diolamine, 2,4-D-dodecylammonium, 2,4-DEB, 2,4-DEP, 2,4-D-ethyl,2,4-D-heptylammonium, 2,4-D-isobutyl, 2,4-D-isoctyl, 2,4-D-isopropyl,2,4-D-isopropylammonium, 2,4-D-lithium, 2,4-D-meptyl, 2,4-D-methyl,2,4-D-octyl, 2,4-D-pentyl, 2,4-D-potassium, 2,4-D-propyl, 2,4-D-sodium,2,4-D-tefuryl, 2,4-D-tetradecylammonium, 2,4-D-triethylammonium,2,4-D-tris(2-hydroxypropyl)ammonium, 2,4-D-trolamine, 2iP,2-methoxyethylmercury chloride, 2-phenylphenol, 3,4-DA, 3,4-DB, 3,4-DP,4-aminopyridine, 4-CPA, 4-CPA-potassium, 4-CPA-sodium, 4-CPB, 4-CPP,4-hydroxyphenethyl alcohol, 8-hydroxyquinoline sulfate,8-phenylmercurioxyquinoline, abamectin, abscisic acid, ACC, acephate,acequinocyl, acetamiprid, acethion, acetochlor, acetophos, acetoprole,acibenzolar, acibenzolar-S-methyl, acifluorfen, acifluorfen-methyl,acifluorfen-sodium, aclonifen, acrep, acrinathrin, acrolein,acrylonitrile, acypetacs, acypetacs-copper, acypetacs-zinc, alachlor,alanycarb, albendazole, aldicarb, aldimorph, aldoxycarb, aldrin,allethrin, allicin, allidochlor, allosamidin, alloxydim,alloxydim-sodium, allyl alcohol, allyxycarb, alorac, alpha-cypermethrin,alpha-endosulfan, ametoctradin, ametridione, ametryn, amibuzin,amicarbazone, amicarthiazol, amidithion, amidoflumet, amidosulfuron,aminocarb, aminocyclopyrachlor, aminocyclopyrachlor-methyl,aminocyclopyrachlor-potassium, aminopyralid, aminopyralid-potassium,aminopyralid-tris(2-hydroxypropyl)ammonium, amiprofos-methyl,amiprophos, amisulbrom, amiton, amiton oxalate, amitraz, amitrole,ammonium sulfamate, ammonium α-naphthaleneacetate, amobam, ampropylfos,anabasine, ancymidol, anilazine, anilofos, anisuron, anthraquinone,antu, apholate, aramite, arsenous oxide, asomate, aspirin, asulam,asulam-potassium, asulam-sodium, athidathion, atraton, atrazine,aureofungin, aviglycine, aviglycine hydrochloride, azaconazole,azadirachtin, azafenidin, azamethiphos, azimsulfuron, azinphos-ethyl,azinphos-methyl, aziprotryne, azithiram, azobenzene, azocyclotin,azothoate, azoxystrobin, bachmedesh, barban, barium hexafluorosilicate,barium polysulfide, barthrin, BCPC, beflubutamid, benalaxyl,benalaxyl-M, benazolin, benazolin-dimethylammonium, benazolin-ethyl,benazolin-potassium, bencarbazone, benclothiaz, bendiocarb, benfluralin,benfuracarb, benfuresate, benodanil, benomyl, benoxacor, benoxafos,benquinox, bensulfuron, bensulfuron-methyl, bensulide, bensultap,bentaluron, bentazone, bentazone-sodium, benthiavalicarb,benthiavalicarb-isopropyl, benthiazole, bentranil, benzadox,benzadox-ammonium, benzalkonium chloride, benzamacril,benzamacril-isobutyl, benzamorf, benzfendizone, benzipram,benzobicyclon, benzofenap, benzofluor, benzohydroxamic acid,benzoximate, benzoylprop, benzoylprop-ethyl, benzthiazuron, benzylbenzoate, benzyladenine, berberine, berberine chloride, beta-cyfluthrin,beta-cypermethrin, bethoxazin, bicyclopyrone, bifenazate, bifenox,bifenthrin, bifujunzhi, bilanafos, bilanafos-sodium, binapacryl,bingqingxiao, bioallethrin, bioethanomethrin, biopermethrin,bioresmethrin, biphenyl, bisazir, bismerthiazol, bispyribac,bispyribac-sodium, bistrifluron, bitertanol, bithionol, bixafen,blasticidin-S, borax, Bordeaux mixture, boric acid, boscalid,brassinolide, brassinolide-ethyl, brevicomin, brodifacoum,brofenvalerate, brofluthrinate, bromacil, bromacil-lithium,bromacil-sodium, bromadiolone, bromethalin, bromethrin, bromfenvinfos,bromoacetamide, bromobonil, bromobutide, bromocyclen, bromo-DDT,bromofenoxim, bromophos, bromophos-ethyl, bromopropylate, bromothalonil,bromoxynil, bromoxynil butyrate, bromoxynil heptanoate, bromoxyniloctanoate, bromoxynil-potassium, brompyrazon, bromuconazole, bronopol,bucarpolate, bufencarb, buminafos, bupirimate, buprofezin, Burgundymixture, busulfan, butacarb, butachlor, butafenacil, butamifos,butathiofos, butenachlor, butethrin, buthidazole, buthiobate, buthiuron,butocarboxim, butonate, butopyronoxyl, butoxycarboxim, butralin,butroxydim, buturon, butylamine, butylate, cacodylic acid, cadusafos,cafenstrole, calcium arsenate, calcium chlorate, calcium cyanamide,calcium polysulfide, calvinphos, cambendichlor, camphechlor, camphor,captafol, captan, carbamorph, carbanolate, carbaryl, carbasulam,carbendazim, carbendazim benzenesulfonate, carbendazim sulfite,carbetamide, carbofuran, carbon disulfide, carbon tetrachloride,carbophenothion, carbosulfan, carboxazole, carboxide, carboxin,carfentrazone, carfentrazone-ethyl, carpropamid, cartap, cartaphydrochloride, carvacrol, carvone, CDEA, cellocidin, CEPC, ceralure,Cheshunt mixture, chinomethionat, chitosan, chlobenthiazone,chlomethoxyfen, chloralose, chloramben, chloramben-ammonium,chloramben-diolamine, chloramben-methyl, chloramben-methylammonium,chloramben-sodium, chloramine phosphorus, chloramphenicol,chloraniformethan, chloranil, chloranocryl, chlorantraniliprole,chlorazifop, chlorazifop-propargyl, chlorazine, chlorbenside,chlorbenzuron, chlorbicyclen, chlorbromuron, chlorbufam, chlordane,chlordecone, chlordimeform, chlordimeform hydrochloride,chlorempenthrin, chlorethoxyfos, chloreturon, chlorfenac,chlorfenac-ammonium, chlorfenac-sodium, chlorfenapyr, chlorfenazole,chlorfenethol, chlorfenprop, chlorfenson, chlorfensulphide,chlorfenvinphos, chlorfluazuron, chlorflurazole, chlorfluren,chlorfluren-methyl, chlorflurenol, chlorflurenol-methyl, chloridazon,chlorimuron, chlorimuron-ethyl, chlormephos, chlormequat, chlormequatchloride, chlornidine, chlornitrofen, chlorobenzilate,chlorodinitronaphthalenes, chloroform, chloromebuform, chloromethiuron,chloroneb, chlorophacinone, chlorophacinone-sodium, chloropicrin,chloropon, chloropropylate, chlorothalonil, chlorotoluron, chloroxuron,chloroxynil, chlorphonium, chlorphonium chloride, chlorphoxim,chlorprazophos, chlorprocarb, chlorpropham, chlorpyrifos,chlorpyrifos-methyl, chlorquinox, chlorsulfuron, chlorthal,chlorthal-dimethyl, chlorthal-monomethyl, chlorthiamid, chlorthiophos,chlozolinate, choline chloride, chromafenozide, cinerin I, cinerin II,cinerins, cinidon-ethyl, cinmethylin, cinosulfuron, ciobutide,cisanilide, cismethrin, clethodim, climbazole, cliodinate, clodinafop,clodinafop-propargyl, cloethocarb, clofencet, clofencet-potassium,clofentezine, clofibric acid, clofop, clofop-isobutyl, clomazone,clomeprop, cloprop, cloproxydim, clopyralid, clopyralid-methyl,clopyralid-olamine, clopyralid-potassium,clopyralid-tris(2-hydroxypropyl)ammonium, cloquintocet,cloquintocet-mexyl, cloransulam, cloransulam-methyl, closantel,clothianidin, clotrimazole, cloxyfonac, cloxyfonac-sodium, CMA,codlelure, colophonate, copper acetate, copper acetoarsenite, copperarsenate, copper carbonate, basic, copper hydroxide, copper naphthenate,copper oleate, copper oxychloride, copper silicate, copper sulfate,copper zinc chromate, coumachlor, coumafuryl, coumaphos, coumatetralyl,coumithoate, coumoxystrobin, CPMC, CPMF, CPPC, credazine, cresol,crimidine, crotamiton, crotoxyphos, crufomate, cryolite, cue-lure,cufraneb, cumyluron, cuprobam, cuprous oxide, curcumenol, cyanamide,cyanatryn, cyanazine, cyanofenphos, cyanophos, cyanthoate,cyantraniliprole, cyazofamid, cybutryne, cyclafuramid, cyclanilide,cyclethrin, cycloate, cycloheximide, cycloprate, cycloprothrin,cyclosulfamuron, cycloxydim, cycluron, cyenopyrafen, cyflufenamid,cyflumetofen, cyfluthrin, cyhalofop, cyhalofop-butyl, cyhalothrin,cyhexatin, cymiazole, cymiazole hydrochloride, cymoxanil, cyometrinil,cypendazole, cypermethrin, cyperquat, cyperquat chloride, cyphenothrin,cyprazine, cyprazole, cyproconazole, cyprodinil, cyprofuram, cypromid,cyprosulfamide, cyromazine, cythioate, daimuron, dalapon,dalapon-calcium, dalapon-magnesium, dalapon-sodium, daminozide,dayoutong, dazomet, dazomet-sodium, DBCP, d-camphor, DCIP, DCPTA, DDT,debacarb, decafentin, decarbofuran, dehydroacetic acid, delachlor,deltamethrin, demephion, demephion-O, demephion-S, demeton,demeton-methyl, demeton-O, demeton-O-methyl, demeton-S,demeton-S-methyl, demeton-S-methylsulphon, desmedipham, desmetryn,d-fanshiluquebingjuzhi, diafenthiuron, dialifos, di-allate, diamidafos,diatomaceous earth, diazinon, dibutyl phthalate, dibutyl succinate,dicamba, dicamba-diglycolamine, dicamba-dimethylammonium,dicamba-diolamine, dicamba-isopropylammonium, dicamba-methyl,dicamba-olamine, dicamba-potassium, dicamba-sodium, dicamba-trolamine,dicapthon, dichlobenil, dichlofenthion, dichlofluanid, dichlone,dichloralurea, dichlorbenzuron, dichlorflurenol, dichlorflurenol-methyl,dichlormate, dichlormid, dichlorophen, dichlorprop,dichlorprop-2-ethylhexyl, dichlorprop-butotyl,dichlorprop-dimethylammonium, dichlorprop-ethylammonium,dichlorprop-isoctyl, dichlorprop-methyl, dichlorprop-P,dichlorprop-P-2-ethylhexyl, dichlorprop-P-dimethylammonium,dichlorprop-potassium, dichlorprop-sodium, dichlorvos, dichlozoline,diclobutrazol, diclocymet, diclofop, diclofop-methyl, diclomezine,diclomezine-sodium, dicloran, diclosulam, dicofol, dicoumarol, dicresyl,dicrotophos, dicyclanil, dicyclonon, dieldrin, dienochlor, diethamquat,diethamquat dichloride, diethatyl, diethatyl-ethyl, diethofencarb,dietholate, diethyl pyrocarbonate, diethyltoluamide, difenacoum,difenoconazole, difenopenten, difenopenten-ethyl, difenoxuron,difenzoquat, difenzoquat metilsulfate, difethialone, diflovidazin,diflubenzuron, diflufenican, diflufenzopyr, diflufenzopyr-sodium,diflumetorim, dikegulac, dikegulac-sodium, dilor, dimatif, dimefluthrin,dimefox, dimefuron, dimepiperate, dimetachlone, dimetan, dimethacarb,dimethachlor, dimethametryn, dimethenamid, dimethenamid-P, dimethipin,dimethirimol, dimethoate, dimethomorph, dimethrin, dimethyl carbate,dimethyl phthalate, dimethylvinphos, dimetilan, dimexano, dimidazon,dimoxystrobin, dinex, dinex-diclexine, dingjunezuo, diniconazole,diniconazole-M, dinitramine, dinobuton, dinocap, dinocap-4, dinocap-6,dinocton, dinofenate, dinopenton, dinoprop, dinosam, dinoseb, dinosebacetate, dinoseb-ammonium, dinoseb-diolamine, dinoseb-sodium,dinoseb-trolamine, dinosulfon, dinotefuran, dinoterb, dinoterb acetate,dinoterbon, diofenolan, dioxabenzofos, dioxacarb, dioxathion,diphacinone, diphacinone-sodium, diphenamid, diphenyl sulfone,diphenylamine, dipropalin, dipropetryn, dipyrithione, diquat, diquatdibromide, disparlure, disul, disulfiram, disulfoton, disul-sodium,ditalimfos, dithianon, dithicrofos, dithioether, dithiopyr, diuron,d-limonene, DMPA, DNOC, DNOC-ammonium, DNOC-potassium, DNOC-sodium,dodemorph, dodemorph acetate, dodemorph benzoate, dodicin, dodicinhydrochloride, dodicin-sodium, dodine, dofenapyn, dominicalure,doramectin, drazoxolon, DSMA, dufulin, EBEP, EBP, ecdysterone,edifenphos, eglinazine, eglinazine-ethyl, emamectin, emamectin benzoate,EMPC, empenthrin, endosulfan, endothal, endothal-diammonium,endothal-dipotassium, endothal-disodium, endothion, endrin,enestroburin, EPN, epocholeone, epofenonane, epoxiconazole,eprinomectin, epronaz, EPTC, erbon, ergocalciferol, erlujixiancaoan,esdépalléthrine, esfenvalerate, esprocarb, etacelasil, etaconazole,etaphos, etem, ethaboxam, ethachlor, ethalfluralin, ethametsulfuron,ethametsulfuron-methyl, ethaprochlor, ethephon, ethidimuron,ethiofencarb, ethiolate, ethion, ethiozin, ethiprole, ethirimol,ethoate-methyl, ethofumesate, ethohexadiol, ethoprophos, ethoxyfen,ethoxyfen-ethyl, ethoxyquin, ethoxysulfuron, ethychlozate, ethylformate, ethyl α-naphthaleneacetate, ethyl-DDD, ethylene, ethylenedibromide, ethylene dichloride, ethylene oxide, ethylicin, ethylmercury2,3-dihydroxypropyl mercaptide, ethylmercury acetate, ethylmercurybromide, ethylmercury chloride, ethylmercury phosphate, etinofen,etnipromid, etobenzanid, etofenprox, etoxazole, etridiazole, etrimfos,eugenol, EXD, famoxadone, famphur, fenamidone, fenaminosulf, fenamiphos,fenapanil, fenarimol, fenasulam, fenazaflor, fenazaquin, fenbuconazole,fenbutatin oxide, fenchlorazole, fenchlorazole-ethyl, fenchlorphos,fenclorim, fenethacarb, fenfluthrin, fenfuram, fenhexamid, fenitropan,fenitrothion, fenjuntong, fenobucarb, fenoprop, fenoprop-3-butoxypropyl,fenoprop-butometyl, fenoprop-butotyl, fenoprop-butyl, fenoprop-isoctyl,fenoprop-methyl, fenoprop-potassium, fenothiocarb, fenoxacrim,fenoxanil, fenoxaprop, fenoxaprop-ethyl, fenoxaprop-P,fenoxaprop-P-ethyl, fenoxasulfone, fenoxycarb, fenpiclonil,fenpirithrin, fenpropathrin, fenpropidin, fenpropimorph, fenpyrazamine,fenpyroximate, fenridazon, fenridazon-potassium, fenridazon-propyl,fenson, fensulfothion, fenteracol, fenthiaprop, fenthiaprop-ethyl,fenthion, fenthion-ethyl, fentin, fentin acetate, fentin chloride,fentin hydroxide, fentrazamide, fentrifanil, fenuron, fenuron TCA,fenvalerate, ferbam, ferimzone, ferrous sulfate, fipronil, flamprop,flamprop-isopropyl, flamprop-M, flamprop-methyl, flamprop-M-isopropyl,flamprop-M-methyl, flazasulfuron, flocoumafen, flometoquin, flonicamid,florasulam, fluacrypyrim, fluazifop, fluazifop-butyl, fluazifop-methyl,fluazifop-P, fluazifop-P-butyl, fluazinam, fluazolate, fluazuron,flubendiamide, flubenzimine, flucarbazone, flucarbazone-sodium,flucetosulfuron, fluchloralin, flucofuron, flucycloxuron, flucythrinate,fludioxonil, fluenetil, fluensulfone, flufenacet, flufenerim,flufenican, flufenoxuron, flufenprox, flufenpyr, flufenpyr-ethyl,flufiprole, flumethrin, flumetover, flumetralin, flumetsulam, flumezin,flumiclorac, flumiclorac-pentyl, flumioxazin, flumipropyn, flumorph,fluometuron, fluopicolide, fluopyram, fluorbenside, fluoridamid,fluoroacetamide, fluorodifen, fluoroglycofen, fluoroglycofen-ethyl,fluoroimide, fluoromidine, fluoronitrofen, fluothiuron, fluotrimazole,fluoxastrobin, flupoxam, flupropacil, flupropadine, flupropanate,flupropanate-sodium, flupyradifurone, flupyrsulfuron,flupyrsulfuron-methyl, flupyrsulfuron-methyl-sodium, fluquinconazole,flurazole, flurenol, flurenol-butyl, flurenol-methyl, fluridone,flurochloridone, fluroxypyr, fluroxypyr-butometyl, fluroxypyr-meptyl,flurprimidol, flursulamid, flurtamone, flusilazole, flusulfamide,fluthiacet, fluthiacet-methyl, flutianil, flutolanil, flutriafol,fluvalinate, fluxapyroxad, fluxofenim, folpet, fomesafen,fomesafen-sodium, fonofos, foramsulfuron, forchlorfenuron, formaldehyde,formetanate, formetanate hydrochloride, formothion, formparanate,formparanate hydrochloride, fosamine, fosamine-ammonium, fosetyl,fosetyl-aluminium, fosmethilan, fospirate, fosthiazate, fosthietan,frontalin, fuberidazole, fucaojing, fucaomi, funaihecaoling,fuphenthiourea, furalane, furalaxyl, furamethrin, furametpyr,furathiocarb, furcarbanil, furconazole, furconazole-cis, furethrin,furfural, furilazole, furmecyclox, furophanate, furyloxyfen,gamma-cyhalothrin, gamma-HCH, genit, gibberellic acid, gibberellins,gliftor, glufosinate, glufosinate-ammonium, glufosinate-P,glufosinate-P-ammonium, glufosinate-P-sodium, glyodin, glyoxime,glyphosate, glyphosate-diammonium, glyphosate-dimethylammonium,glyphosate-isopropylammonium, glyphosate-monoammonium,glyphosate-potassium, glyphosate-sesquisodium, glyphosate-trimesium,glyphosine, gossyplure, grandlure, griseofulvin, guazatine, guazatineacetates, halacrinate, halfenprox, halofenozide, halosafen,halosulfuron, halosulfuron-methyl, haloxydine, haloxyfop,haloxyfop-etotyl, haloxyfop-methyl, haloxyfop-P, haloxyfop-P-etotyl,haloxyfop-P-methyl, haloxyfop-sodium, HCH, hemel, hempa, HEOD,heptachlor, heptenophos, heptopargil, heterophos, hexachloroacetone,hexachlorobenzene, hexachlorobutadiene, hexachlorophene, hexaconazole,hexaflumuron, hexaflurate, hexalure, hexamide, hexazinone, hexylthiofos,hexythiazox, HHDN, holosulf, huancaiwo, huangcaoling, huanjunzuo,hydramethylnon, hydrargaphen, hydrated lime, hydrogen cyanide,hydroprene, hymexazol, hyquincarb, IAA, IBA, icaridin, imazalil,imazalil nitrate, imazalil sulfate, imazamethabenz,imazamethabenz-methyl, imazamox, imazamox-ammonium, imazapic,imazapic-ammonium, imazapyr, imazapyr-isopropylammonium, imazaquin,imazaquin-ammonium, imazaquin-methyl, imazaquin-sodium, imazethapyr,imazethapyr-ammonium, imazosulfuron, imibenconazole, imicyafos,imidacloprid, imidaclothiz, iminoctadine, iminoctadine triacetate,iminoctadine trialbesilate, imiprothrin, inabenfide, indanofan,indaziflam, indoxacarb, inezin, iodobonil, iodocarb, iodomethane,iodosulfuron, iodosulfuron-methyl, iodosulfuron-methyl-sodium,iofensulfuron, iofensulfuron-sodium, ioxynil, ioxynil octanoate,ioxynil-lithium, ioxynil-sodium, ipazine, ipconazole, ipfencarbazone,iprobenfos, iprodione, iprovalicarb, iprymidam, ipsdienol, ipsenol,IPSP, isamidofos, isazofos, isobenzan, isocarbamid, isocarbophos,isocil, isodrin, isofenphos, isofenphos-methyl, isolan, isomethiozin,isonoruron, isopolinate, isoprocarb, isopropalin, isoprothiolane,isoproturon, isopyrazam, isopyrimol, isothioate, isotianil, isouron,isovaledione, isoxaben, isoxachlortole, isoxadifen, isoxadifen-ethyl,isoxaflutole, isoxapyrifop, isoxathion, ivermectin, izopamfos, japonilure, j apothrins, j asmolin I, j asmolin II, jasmonic acid,jiahuangchongzong, jiajizengxiaolin, jiaxiangjunzhi, jiecaowan,jiecaoxi, jodfenphos, juvenile hormone I, juvenile hormone II, juvenilehormone III, kadethrin, karbutilate, karetazan, karetazan-potassium,kasugamycin, kasugamycin hydrochloride, kejunlin, kelevan, ketospiradox,ketospiradox-potassium, kinetin, kinoprene, kresoxim-methyl, kuicaoxi,lactofen, lambda-cyhalothrin, latilure, lead arsenate, lenacil,lepimectin, leptophos, lindane, lineatin, linuron, lirimfos, litlure,looplure, lufenuron, lvdingjunzhi, lvxiancaolin, lythidathion, MAA,malathion, maleic hydrazide, malonoben, maltodextrin, MAMA, mancopper,mancozeb, mandipropamid, maneb, matrine, mazidox, MCPA,MCPA-2-ethylhexyl, MCPA-butotyl, MCPA-butyl, MCPA-dimethylammonium,MCPA-diolamine, MCPA-ethyl, MCPA-isobutyl, MCPA-isoctyl, MCPA-isopropyl,MCPA-methyl, MCPA-olamine, MCPA-potassium, MCPA-sodium, MCPA-thioethyl,MCPA-trolamine, MCPB, MCPB-ethyl, MCPB-methyl, MCPB-sodium, mebenil,mecarbam, mecarbinzid, mecarphon, mecoprop, mecoprop-2-ethylhexyl,mecoprop-dimethylammonium, mecoprop-diolamine, mecoprop-ethadyl,mecoprop-isoctyl, mecoprop-methyl, mecoprop-P, mecoprop-P-2-ethylhexyl,mecoprop-P-dimethylammonium, mecoprop-P-isobutyl, mecoprop-potassium,mecoprop-P-potassium, mecoprop-sodium, mecoprop-trolamine, medimeform,medinoterb, medinoterb acetate, medlure, mefenacet, mefenpyr,mefenpyr-diethyl, mefluidide, mefluidide-diolamine,mefluidide-potassium, megatomoic acid, menazon, mepanipyrim,meperfluthrin, mephenate, mephosfolan, mepiquat, mepiquat chloride,mepiquat pentaborate, mepronil, meptyldinocap, mercuric chloride,mercuric oxide, mercurous chloride, merphos, mesoprazine, mesosulfuron,mesosulfuron-methyl, mesotrione, mesulfen, mesulfenfos, metaflumizone,metalaxyl, metalaxyl-M, metaldehyde, metam, metam-ammonium, metamifop,metamitron, metam-potassium, metam-sodium, metazachlor, metazosulfuron,metazoxolon, metconazole, metepa, metflurazon, methabenzthiazuron,methacrifos, methalpropalin, methamidophos, methasulfocarb, methazole,methfuroxam, methidathion, methiobencarb, methiocarb,methiopyrisulfuron, methiotepa, methiozolin, methiuron, methocrotophos,methometon, methomyl, methoprene, methoprotryne, methoquin-butyl,methothrin, methoxychlor, methoxyfenozide, methoxyphenone, methylapholate, methyl bromide, methyl eugenol, methyl iodide, methylisothiocyanate, methylacetophos, methylchloroform, methyldymron,methylene chloride, methylmercury benzoate, methylmercury dicyandiamide,methylmercury pentachlorophenoxide, methylneodecanamide, metiram,metobenzuron, metobromuron, metofluthrin, metolachlor, metolcarb,metominostrobin, metosulam, metoxadiazone, metoxuron, metrafenone,metribuzin, metsulfovax, metsulfuron, metsulfuron-methyl, mevinphos,mexacarbate, mieshuan, milbemectin, milbemycin oxime, milneb, mipafox,mirex, MNAF, moguchun, molinate, molosultap, monalide, monisouron,monochloroacetic acid, monocrotophos, monolinuron, monosulfuron,monosulfuron-ester, monuron, monuron TCA, morfamquat, morfamquatdichloride, moroxydine, moroxydine hydrochloride, morphothion, morzid,moxidectin, MSMA, muscalure, myclobutanil, myclozolin,N-(ethylmercury)-p-toluenesulphonanilide, nabam, naftalofos, naled,naphthalene, naphthaleneacetamide, naphthalic anhydride, naphthoxyaceticacids, naproanilide, napropamide, naptalam, naptalam-sodium, natamycin,neburon, niclosamide, niclosamide-olamine, nicosulfuron, nicotine,nifluridide, nipyraclofen, nitenpyram, nithiazine, nitralin, nitrapyrin,nitrilacarb, nitrofen, nitrofluorfen, nitrostyrene, nitrothal-isopropyl,norbormide, norflurazon, nornicotine, noruron, novaluron, noviflumuron,nuarimol, OCH, octachlorodipropyl ether, octhilinone, ofurace,omethoate, orbencarb, orfralure, ortho-dichlorobenzene, orthosulfamuron,oryctalure, orysastrobin, oryzalin, osthol, ostramone, oxabetrinil,oxadiargyl, oxadiazon, oxadixyl, oxamate, oxamyl, oxapyrazon,oxapyrazon-dimolamine, oxapyrazon-sodium, oxasulfuron, oxaziclomefone,oxine-copper, oxolinic acid, oxpoconazole, oxpoconazole fumarate,oxycarboxin, oxydemeton-methyl, oxydeprofos, oxydisulfoton, oxyfluorfen,oxymatrine, oxytetracycline, oxytetracycline hydrochloride,paclobutrazol, paichongding, para-dichlorobenzene, parafluron, paraquat,paraquat dichloride, paraquat dimetilsulfate, parathion,parathion-methyl, parinol, pebulate, pefurazoate, pelargonic acid,penconazole, pencycuron, pendimethalin, penflufen, penfluron,penoxsulam, pentachlorophenol, pentanochlor, penthiopyrad, pentmethrin,pentoxazone, perfluidone, permethrin, pethoxamid, phenamacril, phenazineoxide, phenisopham, phenkapton, phenmedipham, phenmedipham-ethyl,phenobenzuron, phenothrin, phenproxide, phenthoate, phenylmercuriurea,phenylmercury acetate, phenylmercury chloride, phenylmercury derivativeof pyrocatechol, phenylmercury nitrate, phenylmercury salicylate,phorate, phosacetim, phosalone, phosdiphen, phosfolan, phosfolan-methyl,phosglycin, phosmet, phosnichlor, phosphamidon, phosphine, phosphocarb,phosphorus, phostin, phoxim, phoxim-methyl, phthalide, picloram,picloram-2-ethylhexyl, picloram-isoctyl, picloram-methyl,picloram-olamine, picloram-potassium, picloram-triethylammonium,picloram-tris(2-hydroxypropyl)ammonium, picolinafen, picoxystrobin,pindone, pindone-sodium, pinoxaden, piperalin, piperonyl butoxide,piperonyl cyclonene, piperophos, piproctanyl, piproctanyl bromide,piprotal, pirimetaphos, pirimicarb, pirimioxyphos, pirimiphos-ethyl,pirimiphos-methyl, plifenate, polycarbamate, polyoxins, polyoxorim,polyoxorim-zinc, polythialan, potassium arsenite, potassium azide,potassium cyanate, potassium gibberellate, potassium naphthenate,potassium polysulfide, potassium thiocyanate, potassiumα-naphthaleneacetate, pp′-DDT, prallethrin, precocene I, precocene II,precocene III, pretilachlor, primidophos, primisulfuron,primisulfuron-methyl, probenazole, prochloraz, prochloraz-manganese,proclonol, procyazine, procymidone, prodiamine, profenofos, profluazol,profluralin, profluthrin, profoxydim, proglinazine, proglinazine-ethyl,prohexadione, prohexadione-calcium, prohydrojasmon, promacyl, promecarb,prometon, prometryn, promurit, propachlor, propamidine, propamidinedihydrochloride, propamocarb, propamocarb hydrochloride, propanil,propaphos, propaquizafop, propargite, proparthrin, propazine,propetamphos, propham, propiconazole, propineb, propisochlor, propoxur,propoxycarbazone, propoxycarbazone-sodium, propyl isome,propyrisulfuron, propyzamide, proquinazid, prosuler, prosulfalin,prosulfocarb, prosulfuron, prothidathion, prothiocarb, prothiocarbhydrochloride, prothioconazole, prothiofos, prothoate, protrifenbute,proxan, proxan-sodium, prynachlor, pydanon, pymetrozine, pyracarbolid,pyraclofos, pyraclonil, pyraclostrobin, pyraflufen, pyraflufen-ethyl,pyrafluprole, pyramat, pyrametostrobin, pyraoxystrobin, pyrasulfotole,pyrazolynate, pyrazophos, pyrazosulfuron, pyrazosulfuron-ethyl,pyrazothion, pyrazoxyfen, pyresmethrin, pyrethrin I, pyrethrin II,pyrethrins, pyribambenz-isopropyl, pyribambenz-propyl, pyribencarb,pyribenzoxim, pyributicarb, pyriclor, pyridaben, pyridafol, pyridalyl,pyridaphenthion, pyridate, pyridinitril, pyrifenox, pyrifluquinazon,pyriftalid, pyrimethanil, pyrimidifen, pyriminobac, pyriminobac-methyl,pyrimisulfan, pyrimitate, pyrinuron, pyriofenone, pyriprole,pyripropanol, pyriproxyfen, pyrithiobac, pyrithiobac-sodium, pyrolan,pyroquilon, pyroxasulfone, pyroxsulam, pyroxychlor, pyroxyfur, quassia,quinacetol, quinacetol sulfate, quinalphos, quinalphos-methyl,quinazamid, quinclorac, quinconazole, quinmerac, quinoclamine,quinonamid, quinothion, quinoxyfen, quintiofos, quintozene, quizalofop,quizalofop-ethyl, quizalofop-P, quizalofop-P-ethyl,quizalofop-P-tefuryl, quwenzhi, quyingding, rabenzazole, rafoxanide,rebemide, resmethrin, rhodethanil, rhodojaponin-III, ribavirin,rimsulfuron, rotenone, ryania, saflufenacil, saijunmao, saisentong,salicylanilide, sanguinarine, santonin, schradan, scilliroside,sebuthylazine, secbumeton, sedaxane, selamectin, semiamitraz,semiamitraz chloride, sesamex, sesamolin, sethoxydim, shuangjiaancaolin,siduron, siglure, silafluofen, silatrane, silica gel, silthiofam,simazine, simeconazole, simeton, simetryn, sintofen, SMA, S-metolachlor,sodium arsenite, sodium azide, sodium chlorate, sodium fluoride, sodiumfluoroacetate, sodium hexafluorosilicate, sodium naphthenate, sodiumorthophenylphenoxide, sodium pentachlorophenoxide, sodium polysulfide,sodium thiocyanate, sodium α-naphthaleneacetate, sophamide, spinetoram,spinosad, spirodiclofen, spiromesifen, spirotetramat, spiroxamine,streptomycin, streptomycin sesquisulfate, strychnine, sulcatol,sulcofuron, sulcofuron-sodium, sulcotrione, sulfallate, sulfentrazone,sulfiram, sulfluramid, sulfometuron, sulfometuron-methyl, sulfosulfuron,sulfotep, sulfoxaflor, sulfoxide, sulfoxime, sulfur, sulfuric acid,sulfuryl fluoride, sulglycapin, sulprofos, sultropen, swep,tau-fluvalinate, tavron, tazimcarb, TCA, TCA-ammonium, TCA-calcium,TCA-ethadyl, TCA-magnesium, TCA-sodium, TDE, tebuconazole, tebufenozide,tebufenpyrad, tebufloquin, tebupirimfos, tebutam, tebuthiuron,tecloftalam, tecnazene, tecoram, teflubenzuron, tefluthrin,tefuryltrione, tembotrione, temephos, tepa, TEPP, tepraloxydim,terallethrin, terbacil, terbucarb, terbuchlor, terbufos, terbumeton,terbuthylazine, terbutryn, tetcyclacis, tetrachloroethane,tetrachlorvinphos, tetraconazole, tetradifon, tetrafluron, tetramethrin,tetramethylfluthrin, tetramine, tetranactin, tetrasul, thallium sulfate,thenylchlor, theta-cypermethrin, thiabendazole, thiacloprid,thiadifluor, thiamethoxam, thiapronil, thiazafluron, thiazopyr,thicrofos, thicyofen, thidiazimin, thidiazuron, thiencarbazone,thiencarbazone-methyl, thifensulfuron, thifensulfuron-methyl,thifluzamide, thiobencarb, thiocarboxime, thiochlorfenphim, thiocyclam,thiocyclam hydrochloride, thiocyclam oxalate, thiodiazole-copper,thiodicarb, thiofanox, thiofluoximate, thiohempa, thiomersal, thiometon,thionazin, thiophanate, thiophanate-methyl, thioquinox,thiosemicarbazide, thiosultap, thiosultap-diammonium,thiosultap-disodium, thiosultap-monosodium, thiotepa, thiram,thuringiensin, tiadinil, tiaojiean, tiocarbazil, tioclorim, tioxymid,tirpate, tolclofos-methyl, tolfenpyrad, tolylfluanid, tolylmercuryacetate, topramezone, tralkoxydim, tralocythrin, tralomethrin,tralopyril, transfluthrin, transpermethrin, tretamine, triacontanol,triadimefon, triadimenol, triafamone, tri-allate, triamiphos,triapenthenol, triarathene, triarimol, triasulfuron, triazamate,triazbutil, triaziflam, triazophos, triazoxide, tribenuron,tribenuron-methyl, tribufos, tributyltin oxide, tricamba, trichlamide,trichlorfon, trichlormetaphos-3, trichloronat, triclopyr,triclopyr-butotyl, triclopyr-ethyl, triclopyr-triethylammonium,tricyclazole, tridemorph, tridiphane, trietazine, trifenmorph,trifenofos, trifloxystrobin, trifloxysulfuron, trifloxysulfuron-sodium,triflumizole, triflumuron, trifluralin, triflusulfuron,triflusulfuron-methyl, trifop, trifop-methyl, trifopsime, triforine,trihydroxytriazine, trimedlure, trimethacarb, trimeturon, trinexapac,trinexapac-ethyl, triprene, tripropindan, triptolide, tritac,triticonazole, tritosulfuron, trunc-call, uniconazole, uniconazole-P,urbacide, uredepa, valerate, validamycin, valifenalate, valone,vamidothion, vangard, vaniliprole, vernolate, vinclozolin, warfarin,warfarin-potassium, warfarin-sodium, xiaochongliulin, xinjunan,xiwojunan, XMC, xylachlor, xylenols, xylylcarb, yishijing, zarilamid,zeatin, zengxiaoan, zeta-cypermethrin, zinc naphthenate, zinc phosphide,zinc thiazole, zineb, ziram, zolaprofos, zoxamide, zuomihuanglong,α-chlorohydrin, α-ecdysone, α-multistriatin, and α-naphthaleneaceticacid. For more information consult the “COMPENDIUM OF PESTICIDE COMMONNAMES” located at http://www.alanwood.net/pesticides/index.html. Alsoconsult “THE PESTICIDE MANUAL” 14th Edition, edited by C D S Tomlin,copyright 2006 by British Crop Production Council, or its prior or morerecent editions.

Biopesticides

Molecules of Formula One may also be used in combination (such as in acompositional mixture, or a simultaneous or sequential application) withone or more biopesticides. The term “biopesticide” is used for microbialbiological pest control agents that are applied in a similar manner tochemical pesticides. Commonly these are bacterial, but there are alsoexamples of fungal control agents, including Trichoderma spp. andAmpelomyces quisqualis (a control agent for grape powdery mildew).Bacillus subtilis are used to control plant pathogens. Weeds and rodentshave also been controlled with microbial agents. One well-knowninsecticide example is Bacillus thuringiensis, a bacterial disease ofLepidoptera, Coleoptera, and Diptera. Because it has little effect onother organisms, it is considered more environmentally friendly thansynthetic pesticides. Biological insecticides include products based on:

1. entomopathogenic fungi (e.g. Metarhizium anisopliae);

2. entomopathogenic nematodes (e.g. Steinernema feltiae); and

3. entomopathogenic viruses (e.g. Cydia pomonella granulovirus).

Other examples of entomopathogenic organisms include, but are notlimited to, baculoviruses, bacteria and other prokaryotic organisms,fungi, protozoa and Microsproridia.

Biologically derived insecticides include, but not limited to, rotenone,veratridine, as well as microbial toxins; insect tolerant or resistantplant varieties; and organisms modified by recombinant DNA technology toeither produce insecticides or to convey an insect resistant property tothe genetically modified organism. In one embodiment, the molecules ofFormula One may be used with one or more biopesticides in the area ofseed treatments and soil amendments. The Manual of Biocontrol Agentsgives a review of the available biological insecticide (and otherbiology-based control) products. Copping L. G. (ed.) (2004). The Manualof Biocontrol Agents (formerly the Biopesticide Manual) 3rd Edition.British Crop Production Council (BCPC), Farnham, Surrey UK.

Other Active Compounds

Molecules of Formula One may also be used in combination (such as in acompositional mixture, or a simultaneous or sequential application) withone or more of the following:

1.3-(4-chloro-2,6-dimethylphenyl)-4-hydroxy-8-oxa-1-azaspiro[4,5]dec-3-en-2-one;2.3-(4′-chloro-2,4-dimethyl[1,1′-biphenyl]-3-yl)-4-hydroxy-8-oxa-1-azaspiro[4,5]dec-3-en-2-one;3. 4-[[(6-chloro-3-pyridinyl)methyl]methylamino]-2(5H)-furanone;4. 4-[[(6-chloro-3-pyridinyl)methyl]cyclopropylamino]-2(5H)-furanone;5.3-chloro-N2-[(1S)-1-methyl-2-(methylsulfonyl)ethyl]-N1-[2-methyl-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]phenyl]-1,2-benzenedicarboxamide;6. 2-cyano-N-ethyl-4-fluoro-3-methoxy-benenesulfonamide;7. 2-cyano-N-ethyl-3-methoxy-benzenesulfonamide;8. 2-cyano-3-difluoromethoxy-N-ethyl-4-fluoro-benzenesulfonamide;9. 2-cyano-3-fluoromethoxy-N-ethyl-benzenesulfonamide;10. 2-cyano-6-fluoro-3-methoxy-N,N-dimethyl-benzenesulfonamide;11. 2-cyano-N-ethyl-6-fluoro-3-methoxy-N-methyl-benzenesulfonamide;12. 2-cyano-3-difluoromethoxy-N,N-dimethylbenzenesulfon-amide;13.3-(difluoromethyl)-N-[2-(3,3-dimethylbutyl)phenyl]-1-methyl-1H-pyrazole-4-carboxamide;14.N-ethyl-2,2-dimethylpropionamide-2-(2,6-dichloro-α,α,α-trifluoro-p-tolyl)hydrazone;15.N-ethyl-2,2-dichloro-1-methylcyclopropane-carboxamide-2-(2,6-dichloro-α,α,α-trifluoro-p-tolyl)hydrazone nicotine;16.O-{(E-)-[2-(4-chloro-phenyl)-2-cyano-1-(2-trifluoromethylphenyl)-vinyl]}S-methylthiocarbonate;17.(E)-N1-[(2-chloro-1,3-thiazol-5-ylmethyl)]-N2-cyano-N1-methylacetamidine;18.1-(6-chloropyridin-3-ylmethyl)-7-methyl-8-nitro-1,2,3,5,6,7-hexahydro-imidazo[1,2-a]pyridin-5-ol;19. 4-[4-chlorophenyl-(2-butylidine-hydrazono)methyl)]phenyl mesylate;and20.N-Ethyl-2,2-dichloro-1-methylcyclopropanecarboxamide-2-(2,6-dichloro-alpha,alpha, alpha-trifluoro-p-tolyl)hydrazone.

Synergistic Mixtures

Molecules of Formula One may be used with certain active compounds toform synergistic mixtures where the mode of action of such compoundscompared to the mode of action of the molecules of Formula One are thesame, similar, or different. Examples of modes of action include, butare not limited to: acetylcholinesterase inhibitor; sodium channelmodulator; chitin biosynthesis inhibitor; GABA and glutamate-gatedchloride channel antagonist; GABA and glutamate-gated chloride channelagonist; acetylcholine receptor agonist; acetylcholine receptorantagonist; MET I inhibitor; Mg-stimulated ATPase inhibitor; nicotinicacetylcholine receptor; Midgut membrane disrupter; oxidativephosphorylation disrupter, and ryanodine receptor (RyRs). Generally,weight ratios of the molecules of Formula One in a synergistic mixturewith another compound are from about 10:1 to about 1:10, in anotherembodiment from about 5:1 to about 1:5, and in another embodiment fromabout 3:1, and in another embodiment about 1:1.

Formulations

A pesticide is rarely suitable for application in its pure form. It isusually necessary to add other substances so that the pesticide can beused at the required concentration and in an appropriate form,permitting ease of application, handling, transportation, storage, andmaximum pesticide activity. Thus, pesticides are formulated into, forexample, baits, concentrated emulsions, dusts, emulsifiableconcentrates, fumigants, gels, granules, microencapsulations, seedtreatments, suspension concentrates, suspoemulsions, tablets, watersoluble liquids, water dispersible granules or dry flowables, wettablepowders, and ultra low volume solutions. For further information onformulation types see “Catalogue of Pesticide Formulation Types andInternational Coding System” Technical Monograph no 2, 5th Edition byCropLife International (2002).

Pesticides are applied most often as aqueous suspensions or emulsionsprepared from concentrated formulations of such pesticides. Suchwater-soluble, water-suspendable, or emulsifiable formulations areeither solids, usually known as wettable powders, or water dispersiblegranules, or liquids usually known as emulsifiable concentrates, oraqueous suspensions. Wettable powders, which may be compacted to formwater dispersible granules, comprise an intimate mixture of thepesticide, a carrier, and surfactants. The concentration of thepesticide is usually from about 10% to about 90% by weight. The carrieris usually selected from among the attapulgite clays, themontmorillonite clays, the diatomaceous earths, or the purifiedsilicates. Effective surfactants, comprising from about 0.5% to about10% of the wettable powder, are found among sulfonated lignins,condensed naphthalenesulfonates, naphthalenesulfonates,alkylbenzenesulfonates, alkyl sulfates, and non-ionic surfactants suchas ethylene oxide adducts of alkyl phenols.

Emulsifiable concentrates of pesticides comprise a convenientconcentration of a pesticide, such as from about 50 to about 500 gramsper liter of liquid dissolved in a carrier that is either a watermiscible solvent or a mixture of water-immiscible organic solvent andemulsifiers. Useful organic solvents include aromatics, especiallyxylenes and petroleum fractions, especially the high-boilingnaphthalenic and olefinic portions of petroleum such as heavy aromaticnaphtha. Other organic solvents may also be used, such as the terpenicsolvents including rosin derivatives, aliphatic ketones such ascyclohexanone, and complex alcohols such as 2-ethoxyethanol. Suitableemulsifiers for emulsifiable concentrates are selected from conventionalanionic and non-ionic surfactants.

Aqueous suspensions comprise suspensions of water-insoluble pesticidesdispersed in an aqueous carrier at a concentration in the range fromabout 5% to about 50% by weight. Suspensions are prepared by finelygrinding the pesticide and vigorously mixing it into a carrier comprisedof water and surfactants. Ingredients, such as inorganic salts andsynthetic or natural gums may also be added, to increase the density andviscosity of the aqueous carrier. It is often most effective to grindand mix the pesticide at the same time by preparing the aqueous mixtureand homogenizing it in an implement such as a sand mill, ball mill, orpiston-type homogenizer.

Pesticides may also be applied as granular compositions that areparticularly useful for applications to the soil. Granular compositionsusually contain from about 0.5% to about 10% by weight of the pesticide,dispersed in a carrier that comprises clay or a similar substance. Suchcompositions are usually prepared by dissolving the pesticide in asuitable solvent and applying it to a granular carrier which has beenpre-formed to the appropriate particle size, in the range of from about0.5 to about 3 mm. Such compositions may also be formulated by making adough or paste of the carrier and compound and crushing and drying toobtain the desired granular particle size.

Dusts containing a pesticide are prepared by intimately mixing thepesticide in powdered form with a suitable dusty agricultural carrier,such as kaolin clay, ground volcanic rock, and the like. Dusts cansuitably contain from about 1% to about 10% of the pesticide. They canbe applied as a seed dressing or as a foliage application with a dustblower machine.

It is equally practical to apply a pesticide in the form of a solutionin an appropriate organic solvent, usually petroleum oil, such as thespray oils, which are widely used in agricultural chemistry.

Pesticides can also be applied in the form of an aerosol composition. Insuch compositions the pesticide is dissolved or dispersed in a carrier,which is a pressure-generating propellant mixture. The aerosolcomposition is packaged in a container from which the mixture isdispensed through an atomizing valve.

Pesticide baits are formed when the pesticide is mixed with food or anattractant or both. When the pests eat the bait they also consume thepesticide. Baits may take the form of granules, gels, flowable powders,liquids, or solids. They can be used in pest harborages.

Fumigants are pesticides that have a relatively high vapor pressure andhence can exist as a gas in sufficient concentrations to kill pests insoil or enclosed spaces. The toxicity of the fumigant is proportional toits concentration and the exposure time. They are characterized by agood capacity for diffusion and act by penetrating the pest'srespiratory system or being absorbed through the pest's cuticle.Fumigants are applied to control stored product pests under gas proofsheets, in gas sealed rooms or buildings or in special chambers.

Pesticides can be microencapsulated by suspending the pesticideparticles or droplets in plastic polymers of various types. By alteringthe chemistry of the polymer or by changing factors in the processing,microcapsules can be formed of various sizes, solubility, wallthicknesses, and degrees of penetrability. These factors govern thespeed with which the active ingredient within is released, which inturn, affects the residual performance, speed of action, and odor of theproduct.

Oil solution concentrates are made by dissolving pesticide in a solventthat will hold the pesticide in solution. Oil solutions of a pesticideusually provide faster knockdown and kill of pests than otherformulations due to the solvents themselves having pesticidal action andthe dissolution of the waxy covering of the integument increasing thespeed of uptake of the pesticide. Other advantages of oil solutionsinclude better storage stability, better penetration of crevices, andbetter adhesion to greasy surfaces.

Another embodiment is an oil-in-water emulsion, wherein the emulsioncomprises oily globules which are each provided with a lamellar liquidcrystal coating and are dispersed in an aqueous phase, wherein each oilyglobule comprises at least one compound which is agriculturally active,and is individually coated with a monolamellar or oligolamellar layercomprising: (1) at least one non-ionic lipophilic surface-active agent,(2) at least one non-ionic hydrophilic surface-active agent and (3) atleast one ionic surface-active agent, wherein the globules having a meanparticle diameter of less than 800 nanometers. Further information onthe embodiment is disclosed in U.S. patent publication 20070027034published Feb. 1, 2007, having patent application Ser. No. 11/495,228.For ease of use, this embodiment will be referred to as “OIWE”.

For further information consult “Insect Pest Management” 2nd Edition byD. Dent, copyright CAB International (2000). Additionally, for moredetailed information consult “Handbook of Pest Control— The Behavior,Life History, and Control of Household Pests” by Arnold Mallis, 9thEdition, copyright 2004 by GIE Media Inc.

Other Formulation Components

Generally, when the molecules disclosed in Formula One are used in aformulation, such formulation can also contain other components. Thesecomponents include, but are not limited to, (this is a non-exhaustiveand non-mutually exclusive list) wetters, spreaders, stickers,penetrants, buffers, sequestering agents, drift reduction agents,compatibility agents, anti-foam agents, cleaning agents, andemulsifiers. A few components are described forthwith.

A wetting agent is a substance that when added to a liquid increases thespreading or penetration power of the liquid by reducing the interfacialtension between the liquid and the surface on which it is spreading.Wetting agents are used for two main functions in agrochemicalformulations: during processing and manufacture to increase the rate ofwetting of powders in water to make concentrates for soluble liquids orsuspension concentrates; and during mixing of a product with water in aspray tank to reduce the wetting time of wettable powders and to improvethe penetration of water into water-dispersible granules. Examples ofwetting agents used in wettable powder, suspension concentrate, andwater-dispersible granule formulations are: sodium lauryl sulfate;sodium dioctyl sulfosuccinate; alkyl phenol ethoxylates; and aliphaticalcohol ethoxylates.

A dispersing agent is a substance which adsorbs onto the surface ofparticles and helps to preserve the state of dispersion of the particlesand prevents them from reaggregating. Dispersing agents are added toagrochemical formulations to facilitate dispersion and suspension duringmanufacture, and to ensure the particles redisperse into water in aspray tank. They are widely used in wettable powders, suspensionconcentrates and water-dispersible granules. Surfactants that are usedas dispersing agents have the ability to adsorb strongly onto a particlesurface and provide a charged or steric barrier to reaggregation ofparticles. The most commonly used surfactants are anionic, non-ionic, ormixtures of the two types. For wettable powder formulations, the mostcommon dispersing agents are sodium lignosulfonates. For suspensionconcentrates, very good adsorption and stabilization are obtained usingpolyelectrolytes, such as sodium naphthalene sulfonate formaldehydecondensates. Tristyrylphenol ethoxylate phosphate esters are also used.Non-ionics such as alkylarylethylene oxide condensates and EO-PO blockcopolymers are sometimes combined with anionics as dispersing agents forsuspension concentrates. In recent years, new types of very highmolecular weight polymeric surfactants have been developed as dispersingagents. These have very long hydrophobic ‘backbones’ and a large numberof ethylene oxide chains forming the ‘teeth’ of a ‘comb’ surfactant.These high molecular weight polymers can give very good long-termstability to suspension concentrates because the hydrophobic backboneshave many anchoring points onto the particle surfaces. Examples ofdispersing agents used in agrochemical formulations are: sodiumlignosulfonates; sodium naphthalene sulfonate formaldehyde condensates;tristyrylphenol ethoxylate phosphate esters; aliphatic alcoholethoxylates; alkyl ethoxylates; EO-PO block copolymers; and graftcopolymers.

An emulsifying agent is a substance which stabilizes a suspension ofdroplets of one liquid phase in another liquid phase. Without theemulsifying agent the two liquids would separate into two immiscibleliquid phases. The most commonly used emulsifier blends containalkylphenol or aliphatic alcohol with twelve or more ethylene oxideunits and the oil-soluble calcium salt of dodecylbenzenesulfonic acid. Arange of hydrophile-lipophile balance (“HLB”) values from 8 to 18 willnormally provide good stable emulsions. Emulsion stability can sometimesbe improved by the addition of a small amount of an EO-PO blockcopolymer surfactant.

A solubilizing agent is a surfactant which will form micelles in waterat concentrations above the critical micelle concentration. The micellesare then able to dissolve or solubilize water-insoluble materials insidethe hydrophobic part of the micelle. The types of surfactants usuallyused for solubilization are non-ionics, sorbitan monooleates, sorbitanmonooleate ethoxylates, and methyl oleate esters.

Surfactants are sometimes used, either alone or with other additivessuch as mineral or vegetable oils as adjuvants to spray-tank mixes toimprove the biological performance of the pesticide on the target. Thetypes of surfactants used for bioenhancement depend generally on thenature and mode of action of the pesticide. However, they are oftennon-ionics such as: alkyl ethoxylates; linear aliphatic alcoholethoxylates; aliphatic amine ethoxylates.

A carrier or diluent in an agricultural formulation is a material addedto the pesticide to give a product of the required strength. Carriersare usually materials with high absorptive capacities, while diluentsare usually materials with low absorptive capacities. Carriers anddiluents are used in the formulation of dusts, wettable powders,granules and water-dispersible granules.

Organic solvents are used mainly in the formulation of emulsifiableconcentrates, oil-in-water emulsions, suspoemulsions, and ultra lowvolume formulations, and to a lesser extent, granular formulations.Sometimes mixtures of solvents are used. The first main groups ofsolvents are aliphatic paraffinic oils such as kerosene or refinedparaffins. The second main group (and the most common) comprises thearomatic solvents such as xylene and higher molecular weight fractionsof C9 and C10 aromatic solvents. Chlorinated hydrocarbons are useful ascosolvents to prevent crystallization of pesticides when the formulationis emulsified into water. Alcohols are sometimes used as cosolvents toincrease solvent power. Other solvents may include vegetable oils, seedoils, and esters of vegetable and seed oils.

Thickeners or gelling agents are used mainly in the formulation ofsuspension concentrates, emulsions and suspoemulsions to modify therheology or flow properties of the liquid and to prevent separation andsettling of the dispersed particles or droplets. Thickening, gelling,and anti-settling agents generally fall into two categories, namelywater-insoluble particulates and water-soluble polymers. It is possibleto produce suspension concentrate formulations using clays and silicas.Examples of these types of materials, include, but are not limited to,montmorillonite, bentonite, magnesium aluminum silicate, andattapulgite. Water-soluble polysaccharides have been used asthickening-gelling agents for many years. The types of polysaccharidesmost commonly used are natural extracts of seeds and seaweeds or aresynthetic derivatives of cellulose. Examples of these types of materialsinclude, but are not limited to, guar gum; locust bean gum; carrageenam;alginates; methyl cellulose; sodium carboxymethyl cellulose (SCMC);hydroxyethyl cellulose (HEC). Other types of anti-settling agents arebased on modified starches, polyacrylates, polyvinyl alcohol andpolyethylene oxide. Another good anti-settling agent is xanthan gum.

Microorganisms can cause spoilage of formulated products. Thereforepreservation agents are used to eliminate or reduce their effect.Examples of such agents include, but are not limited to: propionic acidand its sodium salt; sorbic acid and its sodium or potassium salts;benzoic acid and its sodium salt; p-hydroxybenzoic acid sodium salt;methyl p-hydroxybenzoate; and 1,2-benzisothiazolin-3-one (BIT).

The presence of surfactants often causes water-based formulations tofoam during mixing operations in production and in application through aspray tank. In order to reduce the tendency to foam, anti-foam agentsare often added either during the production stage or before fillinginto bottles. Generally, there are two types of anti-foam agents, namelysilicones and non-silicones. Silicones are usually aqueous emulsions ofdimethyl polysiloxane, while the non-silicone anti-foam agents arewater-insoluble oils, such as octanol and nonanol, or silica. In bothcases, the function of the anti-foam agent is to displace the surfactantfrom the air-water interface.

“Green” agents (e.g., adjuvants, surfactants, solvents) can reduce theoverall environmental footprint of crop protection formulations. Greenagents are biodegradable and generally derived from natural and/orsustainable sources, e.g. plant and animal sources.

Specific examples are: vegetable oils, seed oils, and esters thereof,also alkoxylated alkyl polyglucosides.

For further information, see “Chemistry and Technology of AgrochemicalFormulations” edited by D. A. Knowles, copyright 1998 by Kluwer AcademicPublishers. Also see “Insecticides in Agriculture andEnvironment—Retrospects and Prospects” by A. S. Perry, I. Yamamoto, I.Ishaaya, and R. Perry, copyright 1998 by Springer-Verlag.

Pests

In general, the molecules of Formula One may be used to control pestse.g. beetles, earwigs, cockroaches, flies. aphids, scales, whiteflies,leafhoppers, ants, wasps, termites, moths, butterflies, lice,grasshoppers, locusts, crickets, fleas, thrips, bristletails, mites,ticks, nematodes, and symphylans.

In another embodiment, the molecules of Formula One may be used tocontrol pests in the Phyla Nematoda and/or Arthropoda.

In another embodiment, the molecules of Formula One may be used tocontrol pests in the Subphyla Chelicerata, Myriapoda, and/or Hexapoda.

In another embodiment, the molecules of Formula One may be used tocontrol pests in the Classes of Arachnida, Symphyla, and/or Insecta.

In another embodiment, the molecules of Formula One may be used tocontrol pests of the Order Anoplura. A non-exhaustive list of particulargenera includes, but is not limited to, Haematopinus spp., Hoplopleuraspp., Linognathus spp., Pediculus spp., and Polyplax spp. Anon-exhaustive list of particular species includes, but is not limitedto, Haematopinus asini, Haematopinus suis, Linognathus setosus,Linognathus ovillus, Pediculus humanus capitis, Pediculus humanushumanus, and Pthirus pubis.

In another embodiment, the molecules of Formula One may be used tocontrol pests in the Order Coleoptera. A non-exhaustive list ofparticular genera includes, but is not limited to, Acanthoscelides spp.,Agriotes spp., Anthonomus spp., Apion spp., Apogonia spp., Aulacophoraspp., Bruchus spp., Cerosterna spp., Cerotoma spp., Ceutorhynchus spp.,Chaetocnema spp., Colaspis spp., Ctenicera spp., Curculio spp.,Cyclocephala spp., Diabrotica spp., Hypera spp., Ips spp., Lyctus spp.,Megascelis spp., Meligethes spp., Otiorhynchus spp., Pantomorus spp.,Phyllophaga spp., Phyllotreta spp., Rhizotrogus spp., Rhynchites spp.,Rhynchophorus spp., Scolytus spp., Sphenophorus spp., Sitophilus spp.,and Tribolium spp. A non-exhaustive list of particular species includes,but is not limited to, Acanthoscelides obtectus, Agrilus planipennis,Anoplophora glabripennis, Anthonomus grandis, Ataenius spretulus,Atomaria linearis, Bothynoderes punctiventris, Bruchus pisorum,Callosobruchus maculatus, Carpophilus hemipterus, Cassida vittata,Cerotoma trifurcata, Ceutorhynchus assimilis, Ceutorhynchus napi,Conoderus scalaris, Conoderus stigmosus, Conotrachelus nenuphar, Cotinisnitida, Crioceris asparagi, Cryptolestes ferrugineus, Cryptolestespusillus, Cryptolestes turcicus, Cylindrocopturus adspersus, Deporausmarginatus, Dermestes lardarius, Dermestes maculatus, Epilachnavarivestis, Faustinus cubae, Hylobius pales, Hypera postica,Hypothenemus hampei, Lasioderma serricorne, Leptinotarsa decemlineata,Liogenys fuscus, Liogenys suturalis, Lissorhoptrus oryzophilus,Maecolaspis joliveti, Melanotus communis, Meligethes aeneus, Melolonthamelolontha, Oberea brevis, Oberea linearis, Oryctes rhinoceros,Oryzaephilus mercator, Oryzaephilus surinamensis, Oulema melanopus,Oulema oryzae, Phyllophaga cuyabana, Popillia japonica, Prostephanustruncatus, Rhyzopertha dominica, Sitona lineatus, Sitophilus granarius,Sitophilus oryzae, Sitophilus zeamais, Stegobium paniceum, Triboliumcastaneum, Tribolium confusum, Trogoderma variabile, and Zabrustenebrioides.

In another embodiment, the molecules of Formula One may be used tocontrol pests of the Order Dermaptera.

In another embodiment, the molecules of Formula One may be used tocontrol pests of the Order Blattaria. A non-exhaustive list ofparticular species includes, but is not limited to, Blattella germanica,Blatta orientalis, Parcoblatta pennsylvanica, Periplaneta americana,Periplaneta australasiae, Periplaneta brunnea, Periplaneta fuliginosa,Pycnoscelus surinamensis, and Supella longipalpa.

In another embodiment, the molecules of Formula One may be used tocontrol pests of the Order Diptera. A non-exhaustive list of particulargenera includes, but is not limited to, Aedes spp., Agromyza spp.,Anastrepha spp., Anopheles spp., Bactrocera spp., Ceratitis spp.,Chrysops spp., Cochliomyia spp., Contarinia spp., Culex spp., Dasineuraspp., Delia spp., Drosophila spp., Fannia spp., Hylemyia spp., Liriomyzaspp., Musca spp., Phorbia spp., Tabanus spp., and Tipula spp. Anon-exhaustive list of particular species includes, but is not limitedto, Agromyza frontella, Anastrepha suspensa, Anastrepha ludens,Anastrepha obliqa, Bactrocera cucurbitae, Bactrocera dorsalis,Bactrocera invadens, Bactrocera zonata, Ceratitis capitata, Dasineurabrassicae, Delia platura, Fannia canicularis, Fannia scalaris,Gasterophilus intestinalis, Gracillia perseae, Haematobia irritans,Hypoderma lineatum, Liriomyza brassicae, Melophagus ovinus, Muscaautumnalis, Musca domestica, Oestrus ovis, Oscinella frit, Pegomyabetae, Psila rosae, Rhagoletis cerasi, Rhagoletis pomonella, Rhagoletismendax, Sitodiplosis mosellana, and Stomoxys calcitrans.

In another embodiment, the molecules of Formula One may be used tocontrol pests of the Order Hemiptera. A non-exhaustive list ofparticular genera includes, but is not limited to, Adelges spp.,Aulacaspis spp., Aphrophora spp., Aphis spp., Bemisia spp., Ceroplastesspp., Chionaspis spp., Chrysomphalus spp., Coccus spp., Empoasca spp.,Lepidosaphes spp., Lagynotomus spp., Lygus spp., Macrosiphum spp.,Nephotettix spp., Nezara spp., Philaenus spp., Phytocoris spp.,Piezodorus spp., Planococcus spp., Pseudococcus spp., Rhopalosiphumspp., Saissetia spp., Therioaphis spp., Toumeyella spp., Toxoptera spp.,Trialeurodes spp., Triatoma spp. and Unaspis spp. A non-exhaustive listof particular species includes, but is not limited to, Acrosternumhilare, Acyrthosiphon pisum, Aleyrodes proletella, Aleurodicusdispersus, Aleurothrixus floccosus, Amrasca biguttula biguttula,Aonidiella aurantii, Aphis gossypii, Aphis glycines, Aphis pomi,Aulacorthum solani, Bemisia argentifolii, Bemisia tabaci, Blissusleucopterus, Brachycorynella asparagi, Brevennia rehi, Brevicorynebrassicae, Calocoris norvegicus, Ceroplastes rubens, Cimex hemipterus,Cimex lectularius, Dagbertusfasciatus, Dichelops furcatus, Diuraphisnoxia, Diaphorina citri, Dysaphis plantaginea, Dysdercus suturellus,Edessa meditabunda, Eriosoma lanigerum, Eurygaster maura, Euschistusheros, Euschistus servus, Helopeltis antonii, Helopeltis theivora,Icerya purchasi, Idioscopus nitidulus, Laodelphax striatellus,Leptocorisa oratorius, Leptocorisa varicornis, Lygus hesperus,Maconellicoccus hirsutus, Macrosiphum euphorbiae, Macrosiphum granarium,Macrosiphum rosae, Macrosteles quadrilineatus, Mahanarvafrimbiolata,Metopolophium dirhodum, Mictis longicornis, Myzus persicae, Nephotettixcinctipes, Neurocolpus longirostris, Nezara viridula, Nilaparvatalugens, Parlatoria pergandii, Parlatoria ziziphi, Peregrinus maidis,Phylloxera vitifoliae, Physokermes piceae, Phytocoris californicus,Phytocoris relativus, Piezodorus guildinii, Poecilocapsus lineatus,Psallus vaccinicola, Pseudacysta perseae, Pseudococcus brevipes,Quadraspidiotus perniciosus, Rhopalosiphum maidis, Rhopalosiphum padi,Saissetia oleae, Scaptocoris castanea, Schizaphis graminum, Sitobionavenae, Sogatella furcifera, Trialeurodes vaporariorum, Trialeurodesabutiloneus, Unaspis yanonensis, and Zulia entrerriana.

In another embodiment, the molecules of Formula One may be used tocontrol pests of the Order Hymenoptera. A non-exhaustive list ofparticular genera includes, but is not limited to, Acromyrmex spp., Attaspp., Camponotus spp., Diprion spp., Formica spp., Monomorium spp.,Neodiprion spp., Pogonomyrmex spp., Polistes spp., Solenopsis spp.,Vespula spp., and Xylocopa spp. A non-exhaustive list of particularspecies includes, but is not limited to, Athalia rosae, Atta texana,Iridomyrmex humilis, Monomorium minimum, Monomorium pharaonis,Solenopsis invicta, Solenopsis geminata, Solenopsis molesta, Solenopsisrichtery, Solenopsis xyloni, and Tapinoma sessile.

In another embodiment, the molecules of Formula One may be used tocontrol pests of the Order Isoptera. A non-exhaustive list of particulargenera includes, but is not limited to, Coptotermes spp., Cornitermesspp., Cryptotermes spp., Heterotermes spp., Kalotermes spp.,Incisitermes spp., Macrotermes spp., Marginitermes spp., Microcerotermesspp., Procornitermes spp., Reticulitermes spp., Schedorhinotermes spp.,and Zootermopsis spp. A non-exhaustive list of particular speciesincludes, but is not limited to, Coptotermes curvignathus, Coptotermesfrenchi, Coptotermes formosanus, Heterotermes aureus, Microtermes obesi,Reticulitermes banyulensis, Reticulitermes grassei, Reticulitermesflavipes, Reticulitermes hageni, Reticulitermes hesperus, Reticulitermessantonensis, Reticulitermes speratus, Reticulitermes tibialis, andReticulitermes virginicus.

In another embodiment, the molecules of Formula One may be used tocontrol pests of the Order Lepidoptera. A non-exhaustive list ofparticular genera includes, but is not limited to, Adoxophyes spp.,Agrotis spp., Argyrotaenia spp., Cacoecia spp., Caloptilia spp., Chilospp., Chrysodeixis spp., Colias spp., Crambus spp., Diaphania spp.,Diatraea spp., Earias spp., Ephestia spp., Epimecis spp., Feltia spp.,Gortyna spp., Helicoverpa spp., Heliothis spp., Indarbela spp.,Lithocolletis spp., Loxagrotis spp., Malacosoma spp., Peridroma spp.,Phyllonorycter spp., Pseudaletia spp., Sesamia spp., Spodoptera spp.,Synanthedon spp., and Yponomeuta spp. A non-exhaustive list ofparticular species includes, but is not limited to, Achaea janata,Adoxophyes orana, Agrotis ipsilon, Alabama argillacea, Amorbia cuneana,Amyelois transitella, Anacamptodes defectaria, Anarsia lineatella,Anomis sabulifera, Anticarsia gemmatalis, Archips argyrospila, Archipsrosana, Argyrotaenia citrana, Autographa gamma, Bonagota cranaodes,Borbo cinnara, Bucculatrix thurberiella, Capua reticulana, Carposinaniponensis, Chlumetia transversa, Choristoneura rosaceana,Cnaphalocrocis medinalis, Conopomorpha cramerella, Cossus cossus, Cydiacaryana, Cydia funebrana, Cydia molesta, Cydia nigricana, Cydiapomonella, Darna diducta, Diatraea saccharalis, Diatraea grandiosella,Earias insulana, Earias vittella, Ecdytolopha aurantianum, Elasmopalpuslignosellus, Ephestia cautella, Ephestia elutella, Ephestia kuehniella,Epinotia aporema, Epiphyas postvittana, Erionota thrax, Eupoeciliaambiguella, Euxoa auxiliaris, Grapholita molesta, Hedylepta indicata,Helicoverpa armigera, Helicoverpa zea, Heliothis virescens, Hellulaundalis, Keiferia lycopersicella, Leucinodes orbonalis, Leucopteracoffeella, Leucoptera malifoliella, Lobesia botrana, Loxagrotisalbicosta, Lymantria dispar, Lyonetia clerkella, Mahasena corbetti,Mamestra brassicae, Maruca testulalis, Metisa plana, Mythimna unipuncta,Neoleucinodes elegantalis, Nymphula depunctalis, Operophtera brumata,Ostrinia nubilalis, Oxydia vesulia, Pandemis cerasana, Pandemisheparana, Papilio demodocus, Pectinophora gossypiella, Peridroma saucia,Perileucoptera coffeella, Phthorimaea operculella, Phyllocnistiscitrella, Pieris rapae, Plathypena scabra, Plodia interpunctella,Plutella xylostella, Polychrosis viteana, Prays endocarpa, Prays oleae,Pseudaletia unipuncta, Pseudoplusia includens, Rachiplusia nu,Scirpophaga incertulas, Sesamia inferens, Sesamia nonagrioides, Setoranitens, Sitotroga cerealella, Sparganothis pilleriana, Spodopteraexigua, Spodoptera frugiperda, Spodoptera eridania, Thecla basilides,Tineola bisselliella, Trichoplusia ni, Tuta absoluta, Zeuzera coffeae,and Zeuzera pyrina.

In another embodiment, the molecules of Formula One may be used tocontrol pests of the Order Mallophaga. A non-exhaustive list ofparticular genera includes, but is not limited to, Anaticola spp.,Bovicola spp., Chelopistes spp., Goniodes spp., Menacanthus spp., andTrichodectes spp. A non-exhaustive list of particular species includes,but is not limited to, Bovicola bovis, Bovicola caprae, Bovicola ovis,Chelopistes meleagridis, Goniodes dissimilis, Goniodes gigas,Menacanthus stramineus, Menopon gallinae, and Trichodectes canis.

In another embodiment, the molecules of Formula One may be used tocontrol pests of the Order Orthoptera. A non-exhaustive list ofparticular genera includes, but is not limited to, Melanoplus spp., andPterophylla spp. A non-exhaustive list of particular species includes,but is not limited to, Anabrus simplex, Gryllotalpa africana,Gryllotalpa australis, Gryllotalpa brachyptera, Gryllotalpa hexadactyla,Locusta migratoria, Microcentrum retinerve, Schistocerca gregaria, andScudderiafurcata.

In another embodiment, the molecules of Formula One may be used tocontrol pests of the Order Siphonaptera. A non-exhaustive list ofparticular species includes, but is not limited to, Ceratophyllusgallinae, Ceratophyllus niger, Ctenocephalides canis, Ctenocephalidesfelis, and Pulex irritans.

In another embodiment, the molecules of Formula One may be used tocontrol pests of the Order Thysanoptera. A non-exhaustive list ofparticular genera includes, but is not limited to, Caliothrips spp.,Frankliniella spp., Scirtothrips spp., and Thrips spp. A non-exhaustivelist of particular sp. includes, but is not limited to, Frankliniellafusca, Frankliniella occidentalis, Frankliniella schultzei,Frankliniella williamsi, Heliothrips haemorrhoidalis, Rhipiphorothripscruentatus, Scirtothrips citri, Scirtothrips dorsalis, and Taeniothripsrhopalantennalis, Thrips hawaiiensis, Thrips nigropilosus, Thripsorientalis, Thrips tabaci.

In another embodiment, the molecules of Formula One may be used tocontrol pests of the Order Thysanura. A non-exhaustive list ofparticular genera includes, but is not limited to, Lepisma spp. andThermobia spp.

In another embodiment, the molecules of Formula One may be used tocontrol pests of the Order Acarina. A non-exhaustive list of particulargenera includes, but is not limited to, Acarus spp., Aculops spp.,Boophilus spp., Demodex spp., Dermacentor spp., Epitrimerus spp.,Eriophyes spp., Ixodes spp., Oligonychus spp., Panonychus spp.,Rhizoglyphus spp., and Tetranychus spp. A non-exhaustive list ofparticular species includes, but is not limited to, Acarapis woodi,Acarus siro, Aceria mangiferae, Aculops lycopersici, Aculus pelekassi,Aculus schlechtendali, Amblyomma americanum, Brevipalpus obovatus,Brevipalpus phoenicis, Dermacentor variabilis, Dermatophagoidespteronyssinus, Eotetranychus carpini, Notoedres cati, Oligonychuscoffeae, Oligonychus ilicis, Panonychus citri, Panonychus ulmi,Phyllocoptruta oleivora, Polyphagotarsonemus latus, Rhipicephalussanguineus, Sarcoptes scabiei, Tegolophus perseaflorae, Tetranychusurticae, and Varroa destructor.

In another embodiment, the molecules of Formula One may be used tocontrol pest of the Order Symphyla. A non-exhaustive list of particularsp. includes, but is not limited to, Scutigerella immaculata.

In another embodiment, the molecules of Formula One may be used tocontrol pests of the Phylum Nematoda. A non-exhaustive list ofparticular genera includes, but is not limited to, Aphelenchoides spp.,Belonolaimus spp., Criconemella spp., Ditylenchus spp., Heterodera spp.,Hirschmanniella spp., Hoplolaimus spp., Meloidogyne spp., Pratylenchusspp., and Radopholus spp. A non-exhaustive list of particular sp.includes, but is not limited to, Dirofilaria immitis, Heterodera zeae,Meloidogyne incognita, Meloidogyne javanica, Onchocerca volvulus,Radopholus similis, and Rotylenchulus reniformis.

For additional information consult “HANDBOOK OF PEST CONTROL—THEBEHAVIOR, LIFE HISTORY, AND CONTROL OF HOUSEHOLD PESTS” by ArnoldMallis, 9th Edition, copyright 2004 by GIE Media Inc.

Applications

Molecules of Formula One are generally used in amounts from about 0.01grams per hectare to about 5000 grams per hectare to provide control.Amounts from about 0.1 grams per hectare to about 500 grams per hectareare generally preferred, and amounts from about 1 gram per hectare toabout 50 grams per hectare are generally more preferred.

The area to which a molecule of Formula One is applied can be any areainhabited (or maybe inhabited, or traversed by) a pest, for example:where crops, trees, fruits, cereals, fodder species, vines, turf andornamental plants, are growing; where domesticated animals are residing;the interior or exterior surfaces of buildings (such as places wheregrains are stored), the materials of construction used in building (suchas impregnated wood), and the soil around buildings. Particular cropareas to use a molecule of Formula One include areas where apples, corn,sunflowers, cotton, soybeans, canola, wheat, rice, sorghum, barley,oats, potatoes, oranges, alfalfa, lettuce, strawberries, tomatoes,peppers, crucifers, pears, tobacco, almonds, sugar beets, beans andother valuable crops are growing or the seeds thereof are going to beplanted. It is also advantageous to use ammonium sulfate with a moleculeof Formula One when growing various plants.

Controlling pests generally means that pest populations, pest activity,or both, are reduced in an area. This can come about when: pestpopulations are repulsed from an area; when pests are incapacitated inor around an area; or pests are exterminated, in whole, or in part, inor around an area. Of course, a combination of these results can occur.Generally, pest populations, activity, or both are desirably reducedmore than fifty percent, preferably more than 90 percent. Generally, thearea is not in or on a human; consequently, the locus is generally anon-human area.

The molecules of Formula One may be used in mixtures, appliedsimultaneously or sequentially, alone or with other compounds to enhanceplant vigor (e.g. to grow a better root system, to better withstandstressful growing conditions). Such other compounds are, for example,compounds that modulate plant ethylene receptors, most notably1-methylcyclopropene (also known as 1-MCP). Furthermore, such moleculesmay be used during times when pest activity is low, such as before theplants that are growing begin to produce valuable agriculturalcommodities. Such times include the early planting season when pestpressure is usually low.

The molecules of Formula One can be applied to the foliar and fruitingportions of plants to control pests. The molecules will either come indirect contact with the pest, or the pest will consume the pesticidewhen eating leaf, fruit mass, or extracting sap, that contains thepesticide. The molecules of Formula One can also be applied to the soil,and when applied in this manner, root and stem feeding pests can becontrolled. The roots can absorb a molecule taking it up into the foliarportions of the plant to control above ground chewing and sap feedingpests.

Generally, with baits, the baits are placed in the ground where, forexample, termites can come into contact with, and/or be attracted to,the bait. Baits can also be applied to a surface of a building,(horizontal, vertical, or slant surface) where, for example, ants,termites, cockroaches, and flies, can come into contact with, and/or beattracted to, the bait. Baits can comprise a molecule of Formula One.

The molecules of Formula One can be encapsulated inside, or placed onthe surface of a capsule. The size of the capsules can range fromnanometer size (about 100-900 nanometers in diameter) to micrometer size(about 10-900 microns in diameter).

Because of the unique ability of the eggs of some pests to resistcertain pesticides, repeated applications of the molecules of FormulaOne may be desirable to control newly emerged larvae.

Systemic movement of pesticides in plants may be utilized to controlpests on one portion of the plant by applying (for example by sprayingan area) the molecules of Formula One to a different portion of theplant. For example, control of foliar-feeding insects can be achieved bydrip irrigation or furrow application, by treating the soil with forexample pre- or post-planting soil drench, or by treating the seeds of aplant before planting.

Seed treatment can be applied to all types of seeds, including thosefrom which plants genetically modified to express specialized traitswill germinate. Representative examples include those expressingproteins toxic to invertebrate pests, such as Bacillus thuringiensis orother insecticidal toxins, those expressing herbicide resistance, suchas “Roundup Ready” seed, or those with “stacked” foreign genesexpressing insecticidal toxins, herbicide resistance,nutrition-enhancement, drought resistance, or any other beneficialtraits. Furthermore, such seed treatments with the molecules of FormulaOne may further enhance the ability of a plant to better withstandstressful growing conditions. This results in a healthier, more vigorousplant, which can lead to higher yields at harvest time. Generally, about1 gram of the molecules of Formula One to about 500 grams per 100,000seeds is expected to provide good benefits, amounts from about 10 gramsto about 100 grams per 100,000 seeds is expected to provide betterbenefits, and amounts from about 25 grams to about 75 grams per 100,000seeds is expected to provide even better benefits.

It should be readily apparent that the molecules of Formula One may beused on, in, or around plants genetically modified to expressspecialized traits, such as Bacillus thuringiensis or other insecticidaltoxins, or those expressing herbicide resistance, or those with“stacked” foreign genes expressing insecticidal toxins, herbicideresistance, nutrition-enhancement, or any other beneficial traits.

The molecules of Formula One may be used for controlling endoparasitesand ectoparasites in the veterinary medicine sector or in the field ofnon-human animal keeping. The molecules of Formula One are applied, suchas by oral administration in the form of, for example, tablets,capsules, drinks, granules, by dermal application in the form of, forexample, dipping, spraying, pouring on, spotting on, and dusting, and byparenteral administration in the form of, for example, an injection.

The molecules of Formula One may also be employed advantageously inlivestock keeping, for example, cattle, sheep, pigs, chickens, andgeese. They may also be employed advantageously in pets such as, horses,dogs, and cats. Particular pests to control would be fleas and ticksthat are bothersome to such animals. Suitable formulations areadministered orally to the animals with the drinking water or feed. Thedosages and formulations that are suitable depend on the species.

The molecules of Formula One may also be used for controlling parasiticworms, especially of the intestine, in the animals listed above.

The molecules of Formula One may also be employed in therapeutic methodsfor human health care. Such methods include, but are limited to, oraladministration in the form of, for example, tablets, capsules, drinks,granules, and by dermal application.

Pests around the world have been migrating to new environments (for suchpest) and thereafter becoming a new invasive species in such newenvironment. The molecules of Formula One may also be used on such newinvasive species to control them in such new environment.

The molecules of Formula One may also be used in an area where plants,such as crops, are growing (e.g. pre-planting, planting, pre-harvesting)and where there are low levels (even no actual presence) of pests thatcan commercially damage such plants. The use of such molecules in sucharea is to benefit the plants being grown in the area. Such benefits,may include, but are not limited to, improving the health of a plant,improving the yield of a plant (e.g. increased biomass and/or increasedcontent of valuable ingredients), improving the vigor of a plant (e.g.improved plant growth and/or greener leaves), improving the quality of aplant (e.g. improved content or composition of certain ingredients), andimproving the tolerance to abiotic and/or biotic stress of the plant.

Before a pesticide can be used or sold commercially, such pesticideundergoes lengthy evaluation processes by various governmentalauthorities (local, regional, state, national, and international).Voluminous data requirements are specified by regulatory authorities andmust be addressed through data generation and submission by the productregistrant or by a third party on the product registrant's behalf, oftenusing a computer with a connection to the World Wide Web. Thesegovernmental authorities then review such data and if a determination ofsafety is concluded, provide the potential user or seller with productregistration approval. Thereafter, in that locality where the productregistration is granted and supported, such user or seller may use orsell such pesticide.

A molecule according to Formula One can be tested to determine itsefficacy against pests. Furthermore, mode of action studies can beconducted to determine if said molecule has a different mode of actionthan other pesticides. Thereafter, such acquired data can bedisseminated, such as by the internet, to third parties.

The headings in this document are for convenience only and must not beused to interpret any portion hereof.

Lengthy table referenced here US20160060245A1-20160303-T00001 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20160060245A1-20160303-T00002 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20160060245A1-20160303-T00003 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20160060245A1-20160303-T00004 Pleaserefer to the end of the specification for access instructions.

LENGTHY TABLES The patent application contains a lengthy table section.A copy of the table is available in electronic form from the USPTO website(http://seqdata.uspto.gov/?pageRequest=docDetail&DocID=US20160060245A1).An electronic copy of the table will also be available from the USPTOupon request and payment of the fee set forth in 37 CFR 1.19(b)(3).

We claim:
 1. A composition comprising a molecule according to

wherein (a) A is either

(b) R1 is H, F, Cl, Br, I, CN, NO₂, substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₂-C₆ alkenyl, substituted or unsubstituted C₁-C₆ alkoxy, substituted or unsubstituted C₂-C₆ alkenyloxy, substituted or unsubstituted C₃-C₁₀ cycloalkyl, substituted or unsubstituted C₃-C₁₀ cycloalkenyl, substituted or unsubstituted C₆-C₂₀ aryl, substituted or unsubstituted C₁-C₂₀ heterocyclyl, OR9, C(=X1)R9, C(=X1)OR9, C(=X1)N(R9)₂, N(R9)₂, N(R9)C(=X1)R9, S(O)_(n)R9, S(O)_(n)OR9, S(O)_(n)N(R9)₂, or R9S(O)_(n)R9, wherein each said R1, which is substituted, has one or more substituents selected from F, Cl, Br, I, CN, NO₂, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₁-C₆ haloalkyl, C₂-C₆ haloalkenyl, C₁-C₆ haloalkyloxy, C₂-C₆ haloalkenyloxy, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkenyl, C₃-C₁₀ halocycloalkyl, C₃-C₁₀ halocycloalkenyl, OR9, S(O)_(n)OR9, C₆-C₂₀ aryl, or C₁-C₂₀ heterocyclyl, (each of which that can be substituted, may optionally be substituted with R9); (c) R2 is H, F, Cl, Br, I, CN, NO₂, substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₂-C₆ alkenyl, substituted or unsubstituted C₁-C₆ alkoxy, substituted or unsubstituted C₂-C₆ alkenyloxy, substituted or unsubstituted C₃-C₁₀ cycloalkyl, substituted or unsubstituted C₃-C₁₀ cycloalkenyl, substituted or unsubstituted C₆-C₂₀ aryl, substituted or unsubstituted C₁-C₂₀ heterocyclyl, OR9, C(=X1)R9, C(=X1)OR9, C(=X1)N(R9)₂, N(R9)₂, N(R9)C(=X1)R9, SR9, S(O)_(n)OR9, or R9S(O)_(n)R9, wherein each said R2, which is substituted, has one or more substituents selected from F, Cl, Br, I, CN, NO₂, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₁-C₆ haloalkyl, C₂-C₆ haloalkenyl, C₁-C₆ haloalkyloxy, C₂-C₆ haloalkenyloxy, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkenyl, C₃-C₁₀ halocycloalkyl, C₃-C₁₀ halocycloalkenyl, OR9, S(O)_(n)OR9, C₆-C₂₀ aryl, or C₁-C₂₀ heterocyclyl, (each of which that can be substituted, may optionally be substituted with R9); (d) R3 is H, F, Cl, Br, I, CN, NO₂, substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₂-C₆ alkenyl, substituted or unsubstituted C₁-C₆ alkoxy, substituted or unsubstituted C₂-C₆ alkenyloxy, substituted or unsubstituted C₃-C₁₀ cycloalkyl, substituted or unsubstituted C₃-C₁₀ cycloalkenyl, substituted or unsubstituted C₆-C₂₀ aryl, substituted or unsubstituted C₁-C₂₀ heterocyclyl, OR9, C(=X1)R9, C(=X1)OR9, C(=X1)N(R9)₂, N(R9)₂, N(R9)C(=X1)R9, SR9, S(O)_(n)OR9, or R9S(O)_(n)R9, wherein each said R3, which is substituted, has one or more substituents selected from F, Cl, Br, I, CN, NO₂, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₁-C₆ haloalkyl, C₂-C₆ haloalkenyl, C₁-C₆ haloalkyloxy, C₂-C₆ haloalkenyloxy, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkenyl, C₃-C₁₀ halocycloalkyl, C₃-C₁₀ halocycloalkenyl, OR9, S(O)_(n)OR9, C₆-C₂₀ aryl, or C₁-C₂₀ heterocyclyl, (each of which that can be substituted, may optionally be substituted with R9); (e) when A is (1) A1 then A1 is either (a) A11

where R4 is H, NO₂, substituted or u8nsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₂-C₆ alkenyl, substituted or unsubstituted C₁-C₆ alkoxy, substituted or unsubstituted C₃-C₁₀ cycloalkyl, substituted or unsubstituted C₃-C₁₀ cycloalkenyl, substituted or unsubstituted C₆-C₂₀ aryl, substituted or unsubstituted C₁-C₂₀ heterocyclyl, C(=X1)R9, C(=X1)OR9, C(=X1)N(R9)₂, N(R9)₂, N(R9)C(=X1)R9, S(O)_(n)OR9, or R9S(O)_(n)R9, wherein each said R4, which is substituted, has one or more substituents selected from F, Cl, Br, I, CN, NO₂, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₁-C₆ haloalkyl, C₂-C₆ haloalkenyl, C₁-C₆ haloalkyloxy, C₂-C₆ haloalkenyloxy, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkenyl, C₃-C₁₀ halocycloalkyl, C₃-C₁₀ halocycloalkenyl, OR9, S(O)_(n)OR9, C₆-C₂₀ aryl, or C₁-C₂₀ heterocyclyl, (each of which that can be substituted, may optionally be substituted with R9), or (b) A12

where R4 is a C₁-C₆ alkyl, (2) A2 then R4 is H, F, Cl, Br, I, CN, NO₂, substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₂-C₆ alkenyl, substituted or unsubstituted C₁-C₆ alkoxy, substituted or unsubstituted C₂-C₆ alkenyloxy, substituted or unsubstituted C₃-C₁₀ cycloalkyl, substituted or unsubstituted C₃-C₁₀ cycloalkenyl, substituted or unsubstituted C₆-C₂₀ aryl, substituted or unsubstituted C₁-C₂₀ heterocyclyl, OR9, C(=X1)R9, C(=X1)OR9, C(=X1)N(R9)₂, N(R9)₂, N(R9)C(=X1)R9, SR9, S(O)_(n)OR9, or R9S(O)_(n)R9, wherein each said R4, which is substituted, has one or more substituents selected from F, Cl, Br, I, CN, NO₂, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₁-C₆ haloalkyl, C₂-C₆ haloalkenyl, C₁-C₆ haloalkyloxy, C₂-C₆ haloalkenyloxy, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkenyl, C₃-C₁₀ halocycloalkyl, C₃-C₁₀ halocycloalkenyl, OR9, S(O)_(n)OR9, C₆-C₂₀ aryl, or C₁-C₂₀ heterocyclyl, (each of which that can be substituted, may optionally be substituted with R9); (f) R5 is H, F, Cl, Br, I, CN, NO₂, substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₂-C₆ alkenyl, substituted or unsubstituted C₁-C₆ alkoxy, substituted or unsubstituted C₂-C₆ alkenyloxy, substituted or unsubstituted C₃-C₁₀ cycloalkyl, substituted or unsubstituted C₃-C₁₀ cycloalkenyl, substituted or unsubstituted C₆-C₂₀ aryl, OR9, C(=X1)R9, C(=X1)OR9, C(=X1)N(R9)₂, N(R9)₂, N(R9)C(=X1)R9, SR9, S(O)_(n)OR9, or R9S(O)_(n)R9, wherein each said R5, which is substituted, has one or more substituents selected from F, Cl, Br, I, CN, NO₂, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₁-C₆ haloalkyl, C₂-C₆ haloalkenyl, C₁-C₆ haloalkyloxy, C₂-C₆ haloalkenyloxy, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkenyl, C₃-C₁₀ halocycloalkyl, C₃-C₁₀ halocycloalkenyl, OR9, S(O)_(n)OR9, or C₆-C₂₀ aryl, (each of which that can be substituted, may optionally be substituted with R9); (g) (1) when A is A1 then R6 is R11, substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₂-C₆ alkenyl, substituted or unsubstituted C₁-C₆ alkoxy, substituted or unsubstituted C₂-C₆ alkenyloxy, substituted or unsubstituted C₃-C₁₀ cycloalkyl, substituted or unsubstituted C₃-C₁₀ cycloalkenyl, substituted or unsubstituted C₆-C₂₀ aryl, substituted or unsubstituted C₁-C₂₀ heterocyclyl, OR9, C(=X1)R9, C(=X1)OR9, C(=X1)N(R9)₂, N(R9)₂, N(R9)C(=X1)R9, SR9, S(O)_(n)OR9, R9S(O)_(n)R9, C₁-C₆ alkyl C₆-C₂₀ aryl (wherein the alkyl and aryl can independently be substituted or unsubstituted), C(=X2)R9, C(=X1)X2R9, R9X2C(=X1)R9, R9X2R9, C(═O)(C₁-C₆ alkyl)S(O)_(n)(C₁-C₆ alkyl), C(═O)(C₁-C₆ alkyl)C(═O)O(C₁-C₆ alkyl), (C₁-C₆ alkyl)OC(═O)(C₆-C₂₀ aryl), (C₁-C₆ alkyl)OC(═O)(C₁-C₆ alkyl), C₁-C₆ alkyl-(C₃-C₁₀ cyclohaloalkyl), or (C₁-C₆ alkenyl)C(═O)O(C₁-C₆ alkyl), or R9X2C(=X1)X2R9, wherein each said R6 (except R11), which is substituted, has one or more substituents selected from F, Cl, Br, I, CN, NO₂, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₁-C₆ haloalkyl, C₂-C₆ haloalkenyl, C₁-C₆ haloalkyloxy, C₂-C₆ haloalkenyloxy, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkenyl, C₃-C₁₀ halocycloalkyl, C₃-C₁₀ halocycloalkenyl, OR9, S(O)_(n)OR9, C₆-C₂₀ aryl, or C₁-C₂₀ heterocyclyl, R9aryl, (each of which that can be substituted, may optionally be substituted with R9), optionally R6 (except R11) and R8 can be connected in a cyclic arrangement, where optionally such arrangement can have one or more heteroatoms selected from O, S, or, N, in the cyclic structure connecting R6 and R8, and (2) when A is A2 then R6 is R11, H, substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₂-C₆ alkenyl, substituted or unsubstituted C₁-C₆ alkoxy, substituted or unsubstituted C₂-C₆ alkenyloxy, substituted or unsubstituted C₃-C₁₀ cycloalkyl, substituted or unsubstituted C₃-C₁₀ cycloalkenyl, substituted or unsubstituted C₆-C₂₀ aryl, substituted or unsubstituted C₁-C₂₀ heterocyclyl, OR9, C(=X1)R9, C(=X1)OR9, C(=X1)N(R9)₂, N(R9)₂, N(R9)C(=X1)R9, SR9, S(O)_(n)OR9, R9S(O)_(n)R9, C₁-C₆ alkyl C₆-C₂₀ aryl (wherein the alkyl and aryl can independently be substituted or unsubstituted), C(=X2)R9, C(=X1)X2R9, R9X2C(=X1)R9, R9X2R9, C(═O)(C₁-C₆ alkyl)S(O)_(n)(C₁-C₆ alkyl), C(═O)(C₁-C₆ alkyl)C(═O)O(C₁-C₆ alkyl), (C₁-C₆ alkyl)OC(═O)(C₆-C₂₀ aryl), (C₁-C₆ alkyl)OC(═O)(C₁-C₆ alkyl), C₁-C₆ alkyl-(C₃-C₁₀ cyclohaloalkyl), or (C₁-C₆ alkenyl)C(═O)O(C₁-C₆ alkyl), or R9X2C(=X1)X2R9, wherein each said R6 (except R11), which is substituted, has one or more substituents selected from F, Cl, Br, I, CN, NO₂, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₁-C₆ haloalkyl, C₂-C₆ haloalkenyl, C₁-C₆ haloalkyloxy, C₂-C₆ haloalkenyloxy, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkenyl, C₃-C₁₀ halocycloalkyl, C₃-C₁₀ halocycloalkenyl, OR9, S(O)_(n)OR9, C₆-C₂₀ aryl, or C₁-C₂₀ heterocyclyl, R9aryl, (each of which that can be substituted, may optionally be substituted with R9), optionally R6 (except R11) and R8 can be connected in a cyclic arrangement, where optionally such arrangement can have one or more heteroatoms selected from O, S, or N, in the cyclic structure connecting R6 and R8; (h) R7 is O, S, NR9, or NOR9; (i) R8 is R13-S(O)_(n)—R13 wherein each R13 is independently selected from substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₂-C₆ alkenyl, substituted or unsubstituted C₁-C₆ alkoxy, substituted or unsubstituted C₂-C₆ alkenyloxy, substituted or unsubstituted C₃-C₁₀ cycloalkyl, substituted or unsubstituted C₃-C₁₀ cycloalkenyl, substituted or unsubstituted C₆-C₂₀ aryl, substituted or unsubstituted C₁-C₂₀ heterocyclyl, substituted or unsubstituted S(O)_(n)C₁-C₆ alkyl, substituted or unsubstituted N(C₁-C₆alkyl)₂, wherein each said substituted alkyl, substituted alkenyl, substituted alkoxy, substituted alkenyloxy, substituted cycloalkyl, substituted cycloalkenyl, substituted aryl, substituted heterocyclyl, has one or more substituents independently selected from F, Cl, Br, I, CN, NO₂, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₁-C₆ haloalkyl, C₂-C₆ haloalkenyl, C₁-C₆ haloalkyloxy, C₂-C₆ haloalkenyloxy, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkenyl, C₃-C₁₀ halocycloalkyl, C₃-C₁₀ halocycloalkenyl, OC₁-C₆ alkyl, OC₁-C₆ haloalkyl, S(O)_(n)C₁-C₆alkyl, S(O)_(n)OC₁-C₆ alkyl, C₆-C₂₀ aryl, or C₁-C₂₀ heterocyclyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, N(R9)S(O)_(n)R9, OR9, N(R9)₂, R9OR9, R9N(R9)₂, R9C(=X1)R9, R9C(=X1)N(R9)₂, N(R9)C(=X1)R9, R9N(R9)C(=X1)R9, S(O)_(n)OR9, R9C(=X1)OR9, R9OC(=X1)R9, R9S(O)_(n)R9, S(O)_(n)R9, oxo, (each of which that can be substituted, may optionally be substituted with R9); (j) R9 is (each independently) H, CN, substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₂-C₆ alkenyl, substituted or unsubstituted C₁-C₆ alkoxy, substituted or unsubstituted C₂-C₆ alkenyloxy, substituted or unsubstituted C₃-C₁₀ cycloalkyl, substituted or unsubstituted C₃-C₁₀ cycloalkenyl, substituted or unsubstituted C₆-C₂₀ aryl, substituted or unsubstituted C₁-C₂₀ heterocyclyl, substituted or unsubstituted S(O)_(n)C₁-C₆ alkyl, substituted or unsubstituted N(C₁-C₆alkyl)₂, wherein each said R9, which is substituted, has one or more substituents selected from F, Cl, Br, I, CN, NO₂, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₁-C₆ haloalkyl, C₂-C₆ haloalkenyl, C₁-C₆ haloalkyloxy, C₂-C₆ haloalkenyloxy, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkenyl, C₃-C₁₀ halocycloalkyl, C₃-C₁₀ halocycloalkenyl, OC₁-C₆ alkyl, OC₁-C₆ haloalkyl, S(O)_(n)C₁-C₆alkyl, S(O)_(n)OC₁-C₆ alkyl, C₆-C₂₀ aryl, or C₁-C₂₀ heterocyclyl; (k) n is 0, 1, or 2; (l) X is N or CR_(n1) where R_(n1) is H, F, Cl, Br, I, CN, NO₂, substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₂-C₆ alkenyl, substituted or unsubstituted C₁-C₆ alkoxy, substituted or unsubstituted C₂-C₆ alkenyloxy, substituted or unsubstituted C₃-C₁₀ cycloalkyl, substituted or unsubstituted C₃-C₁₀ cycloalkenyl, substituted or unsubstituted C₆-C₂₀ aryl, substituted or unsubstituted C₁-C₂₀ heterocyclyl, OR9, C(=X1)R9, C(=X1)OR9, C(=X1)N(R9)₂, N(R9)₂, N(R9)C(=X1)R9, SR9, S(O)_(n)R9, S(O)_(n)OR9, or R9S(O)_(n)R9, wherein each said R_(n1) which is substituted, has one or more substituents selected from F, Cl, Br, I, CN, NO₂, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₁-C₆ haloalkyl, C₂-C₆ haloalkenyl, C₁-C₆ haloalkyloxy, C₂-C₆ haloalkenyloxy, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkenyl, C₃-C₁₀ halocycloalkyl, C₃-C₁₀ halocycloalkenyl, OR9, S(O)_(n)OR9, C₆-C₂₀ aryl, or C₁-C₂₀ heterocyclyl, (each of which that can be substituted, may optionally be substituted with R9); (m) X1 is (each independently) O or S; (n) X2 is (each independently) 0, S, =NR9, or =NOR9; (o) Z is CN, NO₂, C₁-C₆ alkyl(R9), C(=X1)N(R9)₂; (p) R11 is Q₁(C≡C)R12, wherein Q₁ is a bond, substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₂-C₆ alkenyl, substituted or unsubstituted C₂-C₆ alkynyl, substituted or unsubstituted C₃-C₁₀ cycloalkyl, substituted or unsubstituted C₂-C₁₀ cycloalkoxy, substituted or unsubstituted C₁-C₆ alkylOR9, substituted or unsubstituted C₁-C₆ alkylS(O)_(n)R9, substituted or unsubstituted C₁-C₆ alkylS(O)_(n)(=NR9), substituted or unsubstituted C₁-C₆ alkylN(R9) (where (C≡C) is attached directly to the N by a bond), substituted or unsubstituted C₁-C₆ alkylN(R9)₂, substituted or unsubstituted C₂-C₆ alkenyloxy, substituted or unsubstituted C₃-C₁₀ cycloalkenyl, substituted or unsubstituted C₂-C₆ alkylC(=R7)C₀-C₆ alkylR9, substituted or unsubstituted C₂-C₆ alkylC(=R7)OR9, substituted or unsubstituted C₁-C₆ alkylOC₀-C₆ alkylC(=R7)R9, substituted or unsubstituted C₁-C₆ alkylN(R9)(C(=R7)R9), substituted or unsubstituted C₁-C₆ alkylN(R9)(C(=R7)OR9), substituted or unsubstituted C₂-C₆ alkyl C(=R7)C₀-C₆ alkylN(R9) (where (C≡C) is attached directly to the N by a bond), substituted or unsubstituted C₂-C₆alkylC(=R7)C₀-C₆ alkylN(R9)₂, OR9, S(O)_(n)R9, N(R9)R9, substituted or unsubstituted C₆-C₂₀ aryl, substituted or unsubstituted C₁-C₂₀ heterocyclyl, wherein each said Q₁, which is substituted, has one or more substituents selected from F, Cl, Br, I, CN, NO₂, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ haloalkyl, C₂-C₆ haloalkenyl, C₁-C₆ haloalkyloxy, C₂-C₆ haloalkenyloxy, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkenyl, C₃-C₁₀ halocycloalkyl, C₃-C₁₀ halocycloalkenyl, OR9, SR9, S(O)_(n)R9, S(O)_(n)OR9, C₆-C₂₀ aryl, or C₁-C₂₀ heterocyclyl, R9aryl, C₁-C₆alkylOR9, C₁-C₆alkylS(O)_(n)R9, (each of which that can be substituted, may optionally be substituted with R9) optionally Q₁ and R8 can be connected in a cyclic arrangement, where optionally such arrangement can have one or more heteroatoms selected from O, S, or N, in the cyclic structure connecting Q₁ and R8; (q) R12 is Q₁ (except where Q₁ is a bond), F, Cl, Br, I, Si(R9)₃ (where each R9 is independently selected), or R9.
 2. A composition according to claim 1 wherein said molecule said A is A1.
 3. A composition according to claim 1 wherein said molecule said A is A2.
 4. A composition according to claim 1 wherein said molecule said R1 is H.
 5. A composition according to claim 1 wherein said molecule said R2 is H.
 6. A composition according to claim 1 wherein said molecule said R3 is selected from H, or substituted or unsubstituted C₁-C₆ alkyl.
 7. A composition according to claim 1 wherein said molecule said R3 is selected from H or CH₃.
 8. A composition according to claim 1 wherein said molecule when said A is A1 then A1 is A11.
 9. A composition according to claim 1 wherein said molecule when said A is A1, and A1 is A11, then R4 is selected from H, or substituted or unsubstituted C₁-C₆ alkyl, or substituted or unsubstituted C₆-C₂₀ aryl.
 10. A composition according to claim 1 wherein said molecule when said A is A1, and A1 is A11 then R4 is selected from CH₃, CH(CH₃)₂, or phenyl.
 11. A composition according to claim 1 wherein said molecule when said A is A1, and A1 is A12, then R4 is CH₃.
 12. A composition according to claim 1 wherein said molecule when said A is A2 then R4 is selected from H, substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₂-C₆ alkenyl, substituted or unsubstituted C₃-C₁₀ cycloalkyl, substituted or unsubstituted C₆-C₂₀ aryl, wherein each said R4, which is substituted, has one or more substituents selected from F, Cl, Br, or I.
 13. A composition according to claim 1 wherein said molecule when said A is A2 then R4 is H or C₁-C₆ alkyl.
 14. A composition according to claim 1 wherein said molecule when said A is A2 then R4 is H, CH₃, CH₂CH₃, CH═CH₂, cyclopropyl, CH₂Cl, CF₃, or phenyl.
 15. A composition according to claim 1 wherein said molecule when said A is A2 then R4 is Br or Cl.
 16. A composition according to claim 1 wherein said molecule said R5 is selected from H, F, Cl, Br, I, substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₁-C₆ alkoxy.
 17. A composition according to claim 1 wherein said molecule said R5 is selected from H, OCH₂CH₃, F, Cl, Br, or CH₃.
 18. A composition according to claim 1 wherein said molecule said R11 is substituted or unsubstituted C₁-C₆ alkylC≡CR12.
 19. A composition according to claim 1 wherein said molecule said R11 is substituted or unsubstituted C₁-C₆ alkylC≡CH.
 20. A composition according to claim 1 wherein said molecule said R11 is substituted or unsubstituted C₁-C₄ alkylC≡CH.
 21. A composition according to claim 1 wherein said molecule said R11 is substituted or unsubstituted C₁-C₂ alkylC≡CH.
 22. A composition according to claim 1 wherein said molecule said R11 is substituted or unsubstituted CH₂C≡CH.
 23. A composition according to claim 1 wherein said molecule said R7 is O or S.
 24. A composition according to claim 1 wherein said molecule said R8 is selected from CH(CH₃)SCH₂CF₃, CH₂CH₂SCH₂CF₃, CH₂SCH₂CF₃, CH₂SCHClCF₃, CH(CH₂CH₃)SCH₂CF₃, CH(CH₃)SCH₂CHF₂, CH(CH₃)SCH₂CH₂F, CH₂CH₂SCH₂CH₂F, CH(CH₃)S(═O)₂CH₂CF₃, CH(CH₃)S(═O)CH₂CF₃, CH₂CH₂S(═O)CH₂CH₂CF₃, CH₂CH₂S(═O)₂CH₂CH₂CF₃, CH(CH₃)CH₂SCF₃, CH(CH₃)SCH₂CH₂CF₃, and CH₂CH₂SCH₂CH₂CF₃.
 25. A composition according to claim 1 wherein said molecule said R8 is selected from CH(CH₃)CH₂SCH₂(2,2-difluorocyclopropyl), CH₂CH₂SCH₂(2,2-difluorocyclopropyl), CH₂CH₂S(═O)CH₂(2,2-difluorocyclopropyl), CH₂CH₂S(═O)₂CH₂(2,2-difluorocyclopropyl), and CH₂CH(CF₃)SCH₂(2,2-difluorocyclopropyl).
 26. A composition according to claim 1 wherein said molecule said R8 is selected from CH₂CH₂SCH₂CH═CCl₂, CH₂SCH₂CH═CCl₂, CH(CH₃)SCH₂CH═CCl₂, and CH(CH₃)SCH═CHF.CH₂CH₂SCH₂CH₂CF₃, CH₂CH₂S(═O)CH₂CH₂CF₃ and CH₂CH₂S(═O)₂CH₂CH₂CF₃.
 27. A composition according to claim 1 wherein said molecule said R8 is selected from (substituted or unsubstituted C₁-C₆ alkyl)-S(O)_(n)-(substituted or unsubstituted C₁-C₆ alkyl) wherein said substituents on said substituted alkyls are selected from F, Cl, Br, I, CN, NO₂, N(R9)S(O)_(n)R9, OR9, S(O)_(n)OR9, R9S(O)_(n)R9, S(O)_(n)R9, C₆-C₂₀ aryl, or C₁-C₂₀ heterocyclyl, (each of which that can be substituted, may optionally be substituted with R9).
 28. A composition according to claim 1 wherein said molecule said X is CR_(n1) where R_(n1) is H or halo.
 29. A composition according to claim 1 wherein said molecule said X is CR_(n1) where R_(n1) is H or F.
 30. A composition according to claim 1 wherein said molecule said X1 or X2 or both are O.
 31. A composition according to claim 1 wherein said molecule has one of the following structures


32. A composition according to claim 1 further comprising: (a) one or more compounds having acaricidal, algicidal, avicidal, bactericidal, fungicidal, herbicidal, insecticidal, molluscicidal, nematicidal, rodenticidal, or virucidal properties; or (b) one or more compounds that are antifeedants, bird repellents, chemosterilants, herbicide safeners, insect attractants, insect repellents, mammal repellents, mating disrupters, plant activators, plant growth regulators, or synergists; or (c) both (a) and (b).
 33. A composition according to claim 1 wherein further comprising one or more compounds selected from: (3-ethoxypropyl)mercury bromide, 1,2-dichloropropane, 1,3-dichloropropene, 1-methylcyclopropene, 1-naphthol, 2-(octylthio)ethanol, 2,3,5-tri-iodobenzoic acid, 2,3,6-TBA, 2,3,6-TBA-dimethylammonium, 2,3,6-TBA-lithium, 2,3,6-TBA-potassium, 2,3,6-TBA-sodium, 2,4,5-T, 2,4,5-T-2-butoxypropyl, 2,4,5-T-2-ethylhexyl, 2,4,5-T-3-butoxypropyl, 2,4,5-TB, 2,4,5-T-butometyl, 2,4,5-T-butotyl, 2,4,5-T-butyl, 2,4,5-T-isobutyl, 2,4,5-T-isoctyl, 2,4,5-T-isopropyl, 2,4,5-T-methyl, 2,4,5-T-pentyl, 2,4,5-T-sodium, 2,4,5-T-triethylammonium, 2,4,5-T-trolamine, 2,4-D, 2,4-D-2-butoxypropyl, 2,4-D-2-ethylhexyl, 2,4-D-3-butoxypropyl, 2,4-D-ammonium, 2,4-DB, 2,4-DB-butyl, 2,4-DB-dimethylammonium, 2,4-DB-isoctyl, 2,4-DB-potassium, 2,4-DB-sodium, 2,4-D-butotyl, 2,4-D-butyl, 2,4-D-diethylammonium, 2,4-D-dimethylammonium, 2,4-D-diolamine, 2,4-D-dodecylammonium, 2,4-DEB, 2,4-DEP, 2,4-D-ethyl, 2,4-D-heptylammonium, 2,4-D-isobutyl, 2,4-D-isoctyl, 2,4-D-isopropyl, 2,4-D-isopropylammonium, 2,4-D-lithium, 2,4-D-meptyl, 2,4-D-methyl, 2,4-D-octyl, 2,4-D-pentyl, 2,4-D-potassium, 2,4-D-propyl, 2,4-D-sodium, 2,4-D-tefuryl, 2,4-D-tetradecylammonium, 2,4-D-triethylammonium, 2,4-D-tris(2-hydroxypropyl)ammonium, 2,4-D-trolamine, 2iP, 2-methoxyethylmercury chloride, 2-phenylphenol, 3,4-DA, 3,4-DB, 3,4-DP, 4-aminopyridine, 4-CPA, 4-CPA-potassium, 4-CPA-sodium, 4-CPB, 4-CPP, 4-hydroxyphenethyl alcohol, 8-hydroxyquinoline sulfate, 8-phenylmercurioxyquinoline, abamectin, abscisic acid, ACC, acephate, acequinocyl, acetamiprid, acethion, acetochlor, acetophos, acetoprole, acibenzolar, acibenzolar-S-methyl, acifluorfen, acifluorfen-methyl, acifluorfen-sodium, aclonifen, acrep, acrinathrin, acrolein, acrylonitrile, acypetacs, acypetacs-copper, acypetacs-zinc, alachlor, alanycarb, albendazole, aldicarb, aldimorph, aldoxycarb, aldrin, allethrin, allicin, allidochlor, allosamidin, alloxydim, alloxydim-sodium, allyl alcohol, allyxycarb, alorac, alpha-cypermethrin, alpha-endosulfan, ametoctradin, ametridione, ametryn, amibuzin, amicarbazone, amicarthiazol, amidithion, amidoflumet, amidosulfuron, aminocarb, aminocyclopyrachlor, aminocyclopyrachlor-methyl, aminocyclopyrachlor-potassium, aminopyralid, aminopyralid-potassium, aminopyralid-tris(2-hydroxypropyl)ammonium, amiprofos-methyl, amiprophos, amisulbrom, amiton, amiton oxalate, amitraz, amitrole, ammonium sulfamate, ammonium α-naphthaleneacetate, amobam, ampropylfos, anabasine, ancymidol, anilazine, anilofos, anisuron, anthraquinone, antu, apholate, aramite, arsenous oxide, asomate, aspirin, asulam, asulam-potassium, asulam-sodium, athidathion, atraton, atrazine, aureofungin, aviglycine, aviglycine hydrochloride, azaconazole, azadirachtin, azafenidin, azamethiphos, azimsulfuron, azinphos-ethyl, azinphos-methyl, aziprotryne, azithiram, azobenzene, azocyclotin, azothoate, azoxystrobin, bachmedesh, barban, barium hexafluorosilicate, barium polysulfide, barthrin, BCPC, beflubutamid, benalaxyl, benalaxyl-M, benazolin, benazolin-dimethylammonium, benazolin-ethyl, benazolin-potassium, bencarbazone, benclothiaz, bendiocarb, benfluralin, benfuracarb, benfuresate, benodanil, benomyl, benoxacor, benoxafos, benquinox, bensulfuron, bensulfuron-methyl, bensulide, bensultap, bentaluron, bentazone, bentazone-sodium, benthiavalicarb, benthiavalicarb-isopropyl, benthiazole, bentranil, benzadox, benzadox-ammonium, benzalkonium chloride, benzamacril, benzamacril-isobutyl, benzamorf, benzfendizone, benzipram, benzobicyclon, benzofenap, benzofluor, benzohydroxamic acid, benzoximate, benzoylprop, benzoylprop-ethyl, benzthiazuron, benzyl benzoate, benzyladenine, berberine, berberine chloride, beta-cyfluthrin, beta-cypermethrin, bethoxazin, bicyclopyrone, bifenazate, bifenox, bifenthrin, bifujunzhi, bilanafos, bilanafos-sodium, binapacryl, bingqingxiao, bioallethrin, bioethanomethrin, biopermethrin, bioresmethrin, biphenyl, bisazir, bismerthiazol, bispyribac, bispyribac-sodium, bistrifluron, bitertanol, bithionol, bixafen, blasticidin-S, borax, Bordeaux mixture, boric acid, boscalid, brassinolide, brassinolide-ethyl, brevicomin, brodifacoum, brofenvalerate, brofluthrinate, bromacil, bromacil-lithium, bromacil-sodium, bromadiolone, bromethalin, bromethrin, bromfenvinfos, bromoacetamide, bromobonil, bromobutide, bromocyclen, bromo-DDT, bromofenoxim, bromophos, bromophos-ethyl, bromopropylate, bromothalonil, bromoxynil, bromoxynil butyrate, bromoxynil heptanoate, bromoxynil octanoate, bromoxynil-potassium, brompyrazon, bromuconazole, bronopol, bucarpolate, bufencarb, buminafos, bupirimate, buprofezin, Burgundy mixture, busulfan, butacarb, butachlor, butafenacil, butamifos, butathiofos, butenachlor, butethrin, buthidazole, buthiobate, buthiuron, butocarboxim, butonate, butopyronoxyl, butoxycarboxim, butralin, butroxydim, buturon, butylamine, butylate, cacodylic acid, cadusafos, cafenstrole, calcium arsenate, calcium chlorate, calcium cyanamide, calcium polysulfide, calvinphos, cambendichlor, camphechlor, camphor, captafol, captan, carbamorph, carbanolate, carbaryl, carbasulam, carbendazim, carbendazim benzenesulfonate, carbendazim sulfite, carbetamide, carbofuran, carbon disulfide, carbon tetrachloride, carbophenothion, carbosulfan, carboxazole, carboxide, carboxin, carfentrazone, carfentrazone-ethyl, carpropamid, cartap, cartap hydrochloride, carvacrol, carvone, CDEA, cellocidin, CEPC, ceralure, Cheshunt mixture, chinomethionat, chitosan, chlobenthiazone, chlomethoxyfen, chloralose, chloramben, chloramben-ammonium, chloramben-diolamine, chloramben-methyl, chloramben-methylammonium, chloramben-sodium, chloramine phosphorus, chloramphenicol, chloraniformethan, chloranil, chloranocryl, chlorantraniliprole, chlorazifop, chlorazifop-propargyl, chlorazine, chlorbenside, chlorbenzuron, chlorbicyclen, chlorbromuron, chlorbufam, chlordane, chlordecone, chlordimeform, chlordimeform hydrochloride, chlorempenthrin, chlorethoxyfos, chloreturon, chlorfenac, chlorfenac-ammonium, chlorfenac-sodium, chlorfenapyr, chlorfenazole, chlorfenethol, chlorfenprop, chlorfenson, chlorfensulphide, chlorfenvinphos, chlorfluazuron, chlorflurazole, chlorfluren, chlorfluren-methyl, chlorflurenol, chlorflurenol-methyl, chloridazon, chlorimuron, chlorimuron-ethyl, chlormephos, chlormequat, chlormequat chloride, chlornidine, chlornitrofen, chlorobenzilate, chlorodinitronaphthalenes, chloroform, chloromebuform, chloromethiuron, chloroneb, chlorophacinone, chlorophacinone-sodium, chloropicrin, chloropon, chloropropylate, chlorothalonil, chlorotoluron, chloroxuron, chloroxynil, chlorphonium, chlorphonium chloride, chlorphoxim, chlorprazophos, chlorprocarb, chlorpropham, chlorpyrifos, chlorpyrifos-methyl, chlorquinox, chlorsulfuron, chlorthal, chlorthal-dimethyl, chlorthal-monomethyl, chlorthiamid, chlorthiophos, chlozolinate, choline chloride, chromafenozide, cinerin I, cinerin II, cinerins, cinidon-ethyl, cinmethylin, cinosulfuron, ciobutide, cisanilide, cismethrin, clethodim, climbazole, cliodinate, clodinafop, clodinafop-propargyl, cloethocarb, clofencet, clofencet-potassium, clofentezine, clofibric acid, clofop, clofop-isobutyl, clomazone, clomeprop, cloprop, cloproxydim, clopyralid, clopyralid-methyl, clopyralid-olamine, clopyralid-potassium, clopyralid-tris(2-hydroxypropyl)ammonium, cloquintocet, cloquintocet-mexyl, cloransulam, cloransulam-methyl, closantel, clothianidin, clotrimazole, cloxyfonac, cloxyfonac-sodium, CMA, codlelure, colophonate, copper acetate, copper acetoarsenite, copper arsenate, copper carbonate, basic, copper hydroxide, copper naphthenate, copper oleate, copper oxychloride, copper silicate, copper sulfate, copper zinc chromate, coumachlor, coumafuryl, coumaphos, coumatetralyl, coumithoate, coumoxystrobin, CPMC, CPMF, CPPC, credazine, cresol, crimidine, crotamiton, crotoxyphos, crufomate, cryolite, cue-lure, cufraneb, cumyluron, cuprobam, cuprous oxide, curcumenol, cyanamide, cyanatryn, cyanazine, cyanofenphos, cyanophos, cyanthoate, cyantraniliprole, cyazofamid, cybutryne, cyclafuramid, cyclanilide, cyclethrin, cycloate, cycloheximide, cycloprate, cycloprothrin, cyclosulfamuron, cycloxydim, cycluron, cyenopyrafen, cyflufenamid, cyflumetofen, cyfluthrin, cyhalofop, cyhalofop-butyl, cyhalothrin, cyhexatin, cymiazole, cymiazole hydrochloride, cymoxanil, cyometrinil, cypendazole, cypermethrin, cyperquat, cyperquat chloride, cyphenothrin, cyprazine, cyprazole, cyproconazole, cyprodinil, cyprofuram, cypromid, cyprosulfamide, cyromazine, cythioate, daimuron, dalapon, dalapon-calcium, dalapon-magnesium, dalapon-sodium, daminozide, dayoutong, dazomet, dazomet-sodium, DBCP, d-camphor, DCIP, DCPTA, DDT, debacarb, decafentin, decarbofuran, dehydroacetic acid, delachlor, deltamethrin, demephion, demephion-O, demephion-S, demeton, demeton-methyl, demeton-O, demeton-O-methyl, demeton-S, demeton-S-methyl, demeton-S-methylsulphon, desmedipham, desmetryn, d-fanshiluquebingjuzhi, diafenthiuron, dialifos, di-allate, diamidafos, diatomaceous earth, diazinon, dibutyl phthalate, dibutyl succinate, dicamba, dicamba-diglycolamine, dicamba-dimethylammonium, dicamba-diolamine, dicamba-isopropylammonium, dicamba-methyl, dicamba-olamine, dicamba-potassium, dicamba-sodium, dicamba-trolamine, dicapthon, dichlobenil, dichlofenthion, dichlofluanid, dichlone, dichloralurea, dichlorbenzuron, dichlorflurenol, dichlorflurenol-methyl, dichlormate, dichlormid, dichlorophen, dichlorprop, dichlorprop-2-ethylhexyl, dichlorprop-butotyl, dichlorprop-dimethylammonium, dichlorprop-ethylammonium, dichlorprop-isoctyl, dichlorprop-methyl, dichlorprop-P, dichlorprop-P-2-ethylhexyl, dichlorprop-P-dimethylammonium, dichlorprop-potassium, dichlorprop-sodium, dichlorvos, dichlozoline, diclobutrazol, diclocymet, diclofop, diclofop-methyl, diclomezine, diclomezine-sodium, dicloran, diclosulam, dicofol, dicoumarol, dicresyl, dicrotophos, dicyclanil, dicyclonon, dieldrin, dienochlor, diethamquat, diethamquat dichloride, diethatyl, diethatyl-ethyl, diethofencarb, dietholate, diethyl pyrocarbonate, diethyltoluamide, difenacoum, difenoconazole, difenopenten, difenopenten-ethyl, difenoxuron, difenzoquat, difenzoquat metilsulfate, difethialone, diflovidazin, diflubenzuron, diflufenican, diflufenzopyr, diflufenzopyr-sodium, diflumetorim, dikegulac, dikegulac-sodium, dilor, dimatif, dimefluthrin, dimefox, dimefuron, dimepiperate, dimetachlone, dimetan, dimethacarb, dimethachlor, dimethametryn, dimethenamid, dimethenamid-P, dimethipin, dimethirimol, dimethoate, dimethomorph, dimethrin, dimethyl carbate, dimethyl phthalate, dimethylvinphos, dimetilan, dimexano, dimidazon, dimoxystrobin, dinex, dinex-diclexine, dingjunezuo, diniconazole, diniconazole-M, dinitramine, dinobuton, dinocap, dinocap-4, dinocap-6, dinocton, dinofenate, dinopenton, dinoprop, dinosam, dinoseb, dinoseb acetate, dinoseb-ammonium, dinoseb-diolamine, dinoseb-sodium, dinoseb-trolamine, dinosulfon, dinotefuran, dinoterb, dinoterb acetate, dinoterbon, diofenolan, dioxabenzofos, dioxacarb, dioxathion, diphacinone, diphacinone-sodium, diphenamid, diphenyl sulfone, diphenylamine, dipropalin, dipropetryn, dipyrithione, diquat, diquat dibromide, disparlure, disul, disulfiram, disulfoton, disul-sodium, ditalimfos, dithianon, dithicrofos, dithioether, dithiopyr, diuron, d-limonene, DMPA, DNOC, DNOC-ammonium, DNOC-potassium, DNOC-sodium, dodemorph, dodemorph acetate, dodemorph benzoate, dodicin, dodicin hydrochloride, dodicin-sodium, dodine, dofenapyn, dominicalure, doramectin, drazoxolon, DSMA, dufulin, EBEP, EBP, ecdysterone, edifenphos, eglinazine, eglinazine-ethyl, emamectin, emamectin benzoate, EMPC, empenthrin, endosulfan, endothal, endothal-diammonium, endothal-dipotassium, endothal-disodium, endothion, endrin, enestroburin, EPN, epocholeone, epofenonane, epoxiconazole, eprinomectin, epronaz, EPTC, erbon, ergocalciferol, erlujixiancaoan, esdépalléthrine, esfenvalerate, esprocarb, etacelasil, etaconazole, etaphos, etem, ethaboxam, ethachlor, ethalfluralin, ethametsulfuron, ethametsulfuron-methyl, ethaprochlor, ethephon, ethidimuron, ethiofencarb, ethiolate, ethion, ethiozin, ethiprole, ethirimol, ethoate-methyl, ethofumesate, ethohexadiol, ethoprophos, ethoxyfen, ethoxyfen-ethyl, ethoxyquin, ethoxysulfuron, ethychlozate, ethyl formate, ethyl α-naphthaleneacetate, ethyl-DDD, ethylene, ethylene dibromide, ethylene dichloride, ethylene oxide, ethylicin, ethylmercury 2,3-dihydroxypropyl mercaptide, ethylmercury acetate, ethylmercury bromide, ethylmercury chloride, ethylmercury phosphate, etinofen, etnipromid, etobenzanid, etofenprox, etoxazole, etridiazole, etrimfos, eugenol, EXD, famoxadone, famphur, fenamidone, fenaminosulf, fenamiphos, fenapanil, fenarimol, fenasulam, fenazaflor, fenazaquin, fenbuconazole, fenbutatin oxide, fenchlorazole, fenchlorazole-ethyl, fenchlorphos, fenclorim, fenethacarb, fenfluthrin, fenfuram, fenhexamid, fenitropan, fenitrothion, fenjuntong, fenobucarb, fenoprop, fenoprop-3-butoxypropyl, fenoprop-butometyl, fenoprop-butotyl, fenoprop-butyl, fenoprop-isoctyl, fenoprop-methyl, fenoprop-potassium, fenothiocarb, fenoxacrim, fenoxanil, fenoxaprop, fenoxaprop-ethyl, fenoxaprop-P, fenoxaprop-P-ethyl, fenoxasulfone, fenoxycarb, fenpiclonil, fenpirithrin, fenpropathrin, fenpropidin, fenpropimorph, fenpyrazamine, fenpyroximate, fenridazon, fenridazon-potassium, fenridazon-propyl, fenson, fensulfothion, fenteracol, fenthiaprop, fenthiaprop-ethyl, fenthion, fenthion-ethyl, fentin, fentin acetate, fentin chloride, fentin hydroxide, fentrazamide, fentrifanil, fenuron, fenuron TCA, fenvalerate, ferbam, ferimzone, ferrous sulfate, fipronil, flamprop, flamprop-isopropyl, flamprop-M, flamprop-methyl, flamprop-M-isopropyl, flamprop-M-methyl, flazasulfuron, flocoumafen, flometoquin, flonicamid, florasulam, fluacrypyrim, fluazifop, fluazifop-butyl, fluazifop-methyl, fluazifop-P, fluazifop-P-butyl, fluazinam, fluazolate, fluazuron, flubendiamide, flubenzimine, flucarbazone, flucarbazone-sodium, flucetosulfuron, fluchloralin, flucofuron, flucycloxuron, flucythrinate, fludioxonil, fluenetil, fluensulfone, flufenacet, flufenerim, flufenican, flufenoxuron, flufenprox, flufenpyr, flufenpyr-ethyl, flufiprole, flumethrin, flumetover, flumetralin, flumetsulam, flumezin, flumiclorac, flumiclorac-pentyl, flumioxazin, flumipropyn, flumorph, fluometuron, fluopicolide, fluopyram, fluorbenside, fluoridamid, fluoroacetamide, fluorodifen, fluoroglycofen, fluoroglycofen-ethyl, fluoroimide, fluoromidine, fluoronitrofen, fluothiuron, fluotrimazole, fluoxastrobin, flupoxam, flupropacil, flupropadine, flupropanate, flupropanate-sodium, flupyradifurone, flupyrsulfuron, flupyrsulfuron-methyl, flupyrsulfuron-methyl-sodium, fluquinconazole, flurazole, flurenol, flurenol-butyl, flurenol-methyl, fluridone, flurochloridone, fluroxypyr, fluroxypyr-butometyl, fluroxypyr-meptyl, flurprimidol, flursulamid, flurtamone, flusilazole, flusulfamide, fluthiacet, fluthiacet-methyl, flutianil, flutolanil, flutriafol, fluvalinate, fluxapyroxad, fluxofenim, folpet, fomesafen, fomesafen-sodium, fonofos, foramsulfuron, forchlorfenuron, formaldehyde, formetanate, formetanate hydrochloride, formothion, formparanate, formparanate hydrochloride, fosamine, fosamine-ammonium, fosetyl, fosetyl-aluminium, fosmethilan, fospirate, fosthiazate, fosthietan, frontalin, fuberidazole, fucaojing, fucaomi, funaihecaoling, fuphenthiourea, furalane, furalaxyl, furamethrin, furametpyr, furathiocarb, furcarbanil, furconazole, furconazole-cis, furethrin, furfural, furilazole, furmecyclox, furophanate, furyloxyfen, gamma-cyhalothrin, gamma-HCH, genit, gibberellic acid, gibberellins, gliftor, glufosinate, glufosinate-ammonium, glufosinate-P, glufosinate-P-ammonium, glufosinate-P-sodium, glyodin, glyoxime, glyphosate, glyphosate-diammonium, glyphosate-dimethylammonium, glyphosate-isopropylammonium, glyphosate-monoammonium, glyphosate-potassium, glyphosate-sesquisodium, glyphosate-trimesium, glyphosine, gossyplure, grandlure, griseofulvin, guazatine, guazatine acetates, halacrinate, halfenprox, halofenozide, halosafen, halosulfuron, halosulfuron-methyl, haloxydine, haloxyfop, haloxyfop-etotyl, haloxyfop-methyl, haloxyfop-P, haloxyfop-P-etotyl, haloxyfop-P-methyl, haloxyfop-sodium, HCH, hemel, hempa, HEOD, heptachlor, heptenophos, heptopargil, heterophos, hexachloroacetone, hexachlorobenzene, hexachlorobutadiene, hexachlorophene, hexaconazole, hexaflumuron, hexaflurate, hexalure, hexamide, hexazinone, hexylthiofos, hexythiazox, HHDN, holosulf, huancaiwo, huangcaoling, huanjunzuo, hydramethylnon, hydrargaphen, hydrated lime, hydrogen cyanide, hydroprene, hymexazol, hyquincarb, IAA, IBA, icaridin, imazalil, imazalil nitrate, imazalil sulfate, imazamethabenz, imazamethabenz-methyl, imazamox, imazamox-ammonium, imazapic, imazapic-ammonium, imazapyr, imazapyr-isopropylammonium, imazaquin, imazaquin-ammonium, imazaquin-methyl, imazaquin-sodium, imazethapyr, imazethapyr-ammonium, imazosulfuron, imibenconazole, imicyafos, imidacloprid, imidaclothiz, iminoctadine, iminoctadine triacetate, iminoctadine trialbesilate, imiprothrin, inabenfide, indanofan, indaziflam, indoxacarb, inezin, iodobonil, iodocarb, iodomethane, iodosulfuron, iodosulfuron-methyl, iodosulfuron-methyl-sodium, iofensulfuron, iofensulfuron-sodium, ioxynil, ioxynil octanoate, ioxynil-lithium, ioxynil-sodium, ipazine, ipconazole, ipfencarbazone, iprobenfos, iprodione, iprovalicarb, iprymidam, ipsdienol, ipsenol, IPSP, isamidofos, isazofos, isobenzan, isocarbamid, isocarbophos, isocil, isodrin, isofenphos, isofenphos-methyl, isolan, isomethiozin, isonoruron, isopolinate, isoprocarb, isopropalin, isoprothiolane, isoproturon, isopyrazam, isopyrimol, isothioate, isotianil, isouron, isovaledione, isoxaben, isoxachlortole, isoxadifen, isoxadifen-ethyl, isoxaflutole, isoxapyrifop, isoxathion, ivermectin, izopamfos, japonilure, japothrins, jasmolin I, jasmolin II, jasmonic acid, jiahuangchongzong, jiajizengxiaolin, jiaxiangjunzhi, jiecaowan, jiecaoxi, jodfenphos, juvenile hormone I, juvenile hormone II, juvenile hormone III, kadethrin, karbutilate, karetazan, karetazan-potassium, kasugamycin, kasugamycin hydrochloride, kejunlin, kelevan, ketospiradox, ketospiradox-potassium, kinetin, kinoprene, kresoxim-methyl, kuicaoxi, lactofen, lambda-cyhalothrin, latilure, lead arsenate, lenacil, lepimectin, leptophos, lindane, lineatin, linuron, lirimfos, litlure, looplure, lufenuron, lvdingjunzhi, lvxiancaolin, lythidathion, MAA, malathion, maleic hydrazide, malonoben, maltodextrin, MAMA, mancopper, mancozeb, mandipropamid, maneb, matrine, mazidox, MCPA, MCPA-2-ethylhexyl, MCPA-butotyl, MCPA-butyl, MCPA-dimethylammonium, MCPA-diolamine, MCPA-ethyl, MCPA-isobutyl, MCPA-isoctyl, MCPA-isopropyl, MCPA-methyl, MCPA-olamine, MCPA-potassium, MCPA-sodium, MCPA-thioethyl, MCPA-trolamine, MCPB, MCPB-ethyl, MCPB-methyl, MCPB-sodium, mebenil, mecarbam, mecarbinzid, mecarphon, mecoprop, mecoprop-2-ethylhexyl, mecoprop-dimethylammonium, mecoprop-diolamine, mecoprop-ethadyl, mecoprop-isoctyl, mecoprop-methyl, mecoprop-P, mecoprop-P-2-ethylhexyl, mecoprop-P-dimethylammonium, mecoprop-P-isobutyl, mecoprop-potassium, mecoprop-P-potassium, mecoprop-sodium, mecoprop-trolamine, medimeform, medinoterb, medinoterb acetate, medlure, mefenacet, mefenpyr, mefenpyr-diethyl, mefluidide, mefluidide-diolamine, mefluidide-potassium, megatomoic acid, menazon, mepanipyrim, meperfluthrin, mephenate, mephosfolan, mepiquat, mepiquat chloride, mepiquat pentaborate, mepronil, meptyldinocap, mercuric chloride, mercuric oxide, mercurous chloride, merphos, mesoprazine, mesosulfuron, mesosulfuron-methyl, mesotrione, mesulfen, mesulfenfos, metaflumizone, metalaxyl, metalaxyl-M, metaldehyde, metam, metam-ammonium, metamifop, metamitron, metam-potassium, metam-sodium, metazachlor, metazosulfuron, metazoxolon, metconazole, metepa, metflurazon, methabenzthiazuron, methacrifos, methalpropalin, methamidophos, methasulfocarb, methazole, methfuroxam, methidathion, methiobencarb, methiocarb, methiopyrisulfuron, methiotepa, methiozolin, methiuron, methocrotophos, methometon, methomyl, methoprene, methoprotryne, methoquin-butyl, methothrin, methoxychlor, methoxyfenozide, methoxyphenone, methyl apholate, methyl bromide, methyl eugenol, methyl iodide, methyl isothiocyanate, methylacetophos, methylchloroform, methyldymron, methylene chloride, methylmercury benzoate, methylmercury dicyandiamide, methylmercury pentachlorophenoxide, methylneodecanamide, metiram, metobenzuron, metobromuron, metofluthrin, metolachlor, metolcarb, metominostrobin, metosulam, metoxadiazone, metoxuron, metrafenone, metribuzin, metsulfovax, metsulfuron, metsulfuron-methyl, mevinphos, mexacarbate, mieshuan, milbemectin, milbemycin oxime, milneb, mipafox, mirex, MNAF, moguchun, molinate, molosultap, monalide, monisouron, monochloroacetic acid, monocrotophos, monolinuron, monosulfuron, monosulfuron-ester, monuron, monuron TCA, morfamquat, morfamquat dichloride, moroxydine, moroxydine hydrochloride, morphothion, morzid, moxidectin, MSMA, muscalure, myclobutanil, myclozolin, N-(ethylmercury)-p-toluenesulphonanilide, nabam, naftalofos, naled, naphthalene, naphthaleneacetamide, naphthalic anhydride, naphthoxyacetic acids, naproanilide, napropamide, naptalam, naptalam-sodium, natamycin, neburon, niclosamide, niclosamide-olamine, nicosulfuron, nicotine, nifluridide, nipyraclofen, nitenpyram, nithiazine, nitralin, nitrapyrin, nitrilacarb, nitrofen, nitrofluorfen, nitrostyrene, nitrothal-isopropyl, norbormide, norflurazon, nornicotine, noruron, novaluron, noviflumuron, nuarimol, OCH, octachlorodipropyl ether, octhilinone, ofurace, omethoate, orbencarb, orfralure, ortho-dichlorobenzene, orthosulfamuron, oryctalure, orysastrobin, oryzalin, osthol, ostramone, oxabetrinil, oxadiargyl, oxadiazon, oxadixyl, oxamate, oxamyl, oxapyrazon, oxapyrazon-dimolamine, oxapyrazon-sodium, oxasulfuron, oxaziclomefone, oxine-copper, oxolinic acid, oxpoconazole, oxpoconazole fumarate, oxycarboxin, oxydemeton-methyl, oxydeprofos, oxydisulfoton, oxyfluorfen, oxymatrine, oxytetracycline, oxytetracycline hydrochloride, paclobutrazol, paichongding, para-dichlorobenzene, parafluron, paraquat, paraquat dichloride, paraquat dimetilsulfate, parathion, parathion-methyl, parinol, pebulate, pefurazoate, pelargonic acid, penconazole, pencycuron, pendimethalin, penflufen, penfluron, penoxsulam, pentachlorophenol, pentanochlor, penthiopyrad, pentmethrin, pentoxazone, perfluidone, permethrin, pethoxamid, phenamacril, phenazine oxide, phenisopham, phenkapton, phenmedipham, phenmedipham-ethyl, phenobenzuron, phenothrin, phenproxide, phenthoate, phenylmercuriurea, phenylmercury acetate, phenylmercury chloride, phenylmercury derivative of pyrocatechol, phenylmercury nitrate, phenylmercury salicylate, phorate, phosacetim, phosalone, phosdiphen, phosfolan, phosfolan-methyl, phosglycin, phosmet, phosnichlor, phosphamidon, phosphine, phosphocarb, phosphorus, phostin, phoxim, phoxim-methyl, phthalide, picloram, picloram-2-ethylhexyl, picloram-isoctyl, picloram-methyl, picloram-olamine, picloram-potassium, picloram-triethylammonium, picloram-tris(2-hydroxypropyl)ammonium, picolinafen, picoxystrobin, pindone, pindone-sodium, pinoxaden, piperalin, piperonyl butoxide, piperonyl cyclonene, piperophos, piproctanyl, piproctanyl bromide, piprotal, pirimetaphos, pirimicarb, pirimioxyphos, pirimiphos-ethyl, pirimiphos-methyl, plifenate, polycarbamate, polyoxins, polyoxorim, polyoxorim-zinc, polythialan, potassium arsenite, potassium azide, potassium cyanate, potassium gibberellate, potassium naphthenate, potassium polysulfide, potassium thiocyanate, potassium α-naphthaleneacetate, pp′-DDT, prallethrin, precocene I, precocene II, precocene III, pretilachlor, primidophos, primisulfuron, primisulfuron-methyl, probenazole, prochloraz, prochloraz-manganese, proclonol, procyazine, procymidone, prodiamine, profenofos, profluazol, profluralin, profluthrin, profoxydim, proglinazine, proglinazine-ethyl, prohexadione, prohexadione-calcium, prohydrojasmon, promacyl, promecarb, prometon, prometryn, promurit, propachlor, propamidine, propamidine dihydrochloride, propamocarb, propamocarb hydrochloride, propanil, propaphos, propaquizafop, propargite, proparthrin, propazine, propetamphos, propham, propiconazole, propineb, propisochlor, propoxur, propoxycarbazone, propoxycarbazone-sodium, propyl isome, propyrisulfuron, propyzamide, proquinazid, prosuler, prosulfalin, prosulfocarb, prosulfuron, prothidathion, prothiocarb, prothiocarb hydrochloride, prothioconazole, prothiofos, prothoate, protrifenbute, proxan, proxan-sodium, prynachlor, pydanon, pymetrozine, pyracarbolid, pyraclofos, pyraclonil, pyraclostrobin, pyraflufen, pyraflufen-ethyl, pyrafluprole, pyramat, pyrametostrobin, pyraoxystrobin, pyrasulfotole, pyrazolynate, pyrazophos, pyrazosulfuron, pyrazosulfuron-ethyl, pyrazothion, pyrazoxyfen, pyresmethrin, pyrethrin I, pyrethrin II, pyrethrins, pyribambenz-isopropyl, pyribambenz-propyl, pyribencarb, pyribenzoxim, pyributicarb, pyriclor, pyridaben, pyridafol, pyridalyl, pyridaphenthion, pyridate, pyridinitril, pyrifenox, pyrifluquinazon, pyriftalid, pyrimethanil, pyrimidifen, pyriminobac, pyriminobac-methyl, pyrimisulfan, pyrimitate, pyrinuron, pyriofenone, pyriprole, pyripropanol, pyriproxyfen, pyrithiobac, pyrithiobac-sodium, pyrolan, pyroquilon, pyroxasulfone, pyroxsulam, pyroxychlor, pyroxyfur, quassia, quinacetol, quinacetol sulfate, quinalphos, quinalphos-methyl, quinazamid, quinclorac, quinconazole, quinmerac, quinoclamine, quinonamid, quinothion, quinoxyfen, quintiofos, quintozene, quizalofop, quizalofop-ethyl, quizalofop-P, quizalofop-P-ethyl, quizalofop-P-tefuryl, quwenzhi, quyingding, rabenzazole, rafoxanide, rebemide, resmethrin, rhodethanil, rhodojaponin-III, ribavirin, rimsulfuron, rotenone, ryania, saflufenacil, saijunmao, saisentong, salicylanilide, sanguinarine, santonin, schradan, scilliroside, sebuthylazine, secbumeton, sedaxane, selamectin, semiamitraz, semiamitraz chloride, sesamex, sesamolin, sethoxydim, shuangjiaancaolin, siduron, siglure, silafluofen, silatrane, silica gel, silthiofam, simazine, simeconazole, simeton, simetryn, sintofen, SMA, S-metolachlor, sodium arsenite, sodium azide, sodium chlorate, sodium fluoride, sodium fluoroacetate, sodium hexafluorosilicate, sodium naphthenate, sodium orthophenylphenoxide, sodium pentachlorophenoxide, sodium polysulfide, sodium thiocyanate, sodium α-naphthaleneacetate, sophamide, spinetoram, spinosad, spirodiclofen, spiromesifen, spirotetramat, spiroxamine, streptomycin, streptomycin sesquisulfate, strychnine, sulcatol, sulcofuron, sulcofuron-sodium, sulcotrione, sulfallate, sulfentrazone, sulfiram, sulfluramid, sulfometuron, sulfometuron-methyl, sulfosulfuron, sulfotep, sulfoxaflor, sulfoxide, sulfoxime, sulfur, sulfuric acid, sulfuryl fluoride, sulglycapin, sulprofos, sultropen, swep, tau-fluvalinate, tavron, tazimcarb, TCA, TCA-ammonium, TCA-calcium, TCA-ethadyl, TCA-magnesium, TCA-sodium, TDE, tebuconazole, tebufenozide, tebufenpyrad, tebufloquin, tebupirimfos, tebutam, tebuthiuron, tecloftalam, tecnazene, tecoram, teflubenzuron, tefluthrin, tefuryltrione, tembotrione, temephos, tepa, TEPP, tepraloxydim, terallethrin, terbacil, terbucarb, terbuchlor, terbufos, terbumeton, terbuthylazine, terbutryn, tetcyclacis, tetrachloroethane, tetrachlorvinphos, tetraconazole, tetradifon, tetrafluron, tetramethrin, tetramethylfluthrin, tetramine, tetranactin, tetrasul, thallium sulfate, thenylchlor, theta-cypermethrin, thiabendazole, thiacloprid, thiadifluor, thiamethoxam, thiapronil, thiazafluron, thiazopyr, thicrofos, thicyofen, thidiazimin, thidiazuron, thiencarbazone, thiencarbazone-methyl, thifensulfuron, thifensulfuron-methyl, thifluzamide, thiobencarb, thiocarboxime, thiochlorfenphim, thiocyclam, thiocyclam hydrochloride, thiocyclam oxalate, thiodiazole-copper, thiodicarb, thiofanox, thiofluoximate, thiohempa, thiomersal, thiometon, thionazin, thiophanate, thiophanate-methyl, thioquinox, thiosemicarbazide, thiosultap, thiosultap-diammonium, thiosultap-disodium, thiosultap-monosodium, thiotepa, thiram, thuringiensin, tiadinil, tiaojiean, tiocarbazil, tioclorim, tioxymid, tirpate, tolclofos-methyl, tolfenpyrad, tolylfluanid, tolylmercury acetate, topramezone, tralkoxydim, tralocythrin, tralomethrin, tralopyril, transfluthrin, transpermethrin, tretamine, triacontanol, triadimefon, triadimenol, triafamone, tri-allate, triamiphos, triapenthenol, triarathene, triarimol, triasulfuron, triazamate, triazbutil, triaziflam, triazophos, triazoxide, tribenuron, tribenuron-methyl, tribufos, tributyltin oxide, tricamba, trichlamide, trichlorfon, trichlormetaphos-3, trichloronat, triclopyr, triclopyr-butotyl, triclopyr-ethyl, triclopyr-triethylammonium, tricyclazole, tridemorph, tridiphane, trietazine, trifenmorph, trifenofos, trifloxystrobin, trifloxysulfuron, trifloxysulfuron-sodium, triflumizole, triflumuron, trifluralin, triflusulfuron, triflusulfuron-methyl, trifop, trifop-methyl, trifopsime, triforine, trihydroxytriazine, trimedlure, trimethacarb, trimeturon, trinexapac, trinexapac-ethyl, triprene, tripropindan, triptolide, tritac, triticonazole, tritosulfuron, trunc-call, uniconazole, uniconazole-P, urbacide, uredepa, valerate, validamycin, valifenalate, valone, vamidothion, vangard, vaniliprole, vernolate, vinclozolin, warfarin, warfarin-potassium, warfarin-sodium, xiaochongliulin, xinjunan, xiwojunan, XMC, xylachlor, xylenols, xylylcarb, yishijing, zarilamid, zeatin, zengxiaoan, zeta-cypermethrin, zinc naphthenate, zinc phosphide, zinc thiazole, zineb, ziram, zolaprofos, zoxamide, zuomihuanglong, α-chlorohydrin, α-ecdysone, α-multistriatin, and α-naphthaleneacetic acid.
 34. A composition according to claim 1 further comprising an agriculturally acceptable carrier.
 35. A composition according to claim 1 wherein said molecule is in the form of a pesticidally acceptable acid addition salt.
 36. A composition according to claim 1 wherein said molecule is in the form of a salt derivative.
 37. A composition according to claim 1 wherein said molecule is in the form a hydrate.
 38. A composition according to claim 1 wherein said molecule is a resolved stereoisomer.
 39. A composition according to claim 1 wherein said molecule is in the form a crystal polymorph.
 40. A composition according to claim 1 wherein said molecule has a ²H in place of ¹H.
 41. A composition according to claim 1 wherein said molecule has a ¹³C in place of a ¹²C.
 42. A composition according to claim 1 further comprising a biopesticide.
 43. A composition according to claim 1 further comprising one or more of the following compounds: (a) 3-(4-chloro-2,6-dimethylphenyl)-4-hydroxy-8-oxa-1-azaspiro[4,5]dec-3-en-2-one; (b) 3-(4′-chloro-2,4-dimethyl[1,1′-biphenyl]-3-yl)-4-hydroxy-8-oxa-1-azaspiro[4,5]dec-3-en-2-one; (c) 4-[[(6-chloro-3-pyridinyl)methyl]methylamino]-2(5H)-furanone; (d) 4-[[(6-chloro-3-pyridinyl)methyl]cyclopropylamino]-2(5H)-furanone; (e) 3-chloro-N2-[(1S)-1-methyl-2-(methylsulfonyl)ethyl]-N1-[2-methyl-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]phenyl]-1,2-benzenedicarboxamide; (f) 2-cyano-N-ethyl-4-fluoro-3-methoxy-benenesulfonamide; (g) 2-cyano-N-ethyl-3-methoxy-benzenesulfonamide; (h) 2-cyano-3-difluoromethoxy-N-ethyl-4-fluoro-benzenesulfonamide; (i) 2-cyano-3-fluoromethoxy-N-ethyl-benzenesulfonamide; (j) 2-cyano-6-fluoro-3-methoxy-N,N-dimethyl-benzenesulfonamide; (k) 2-cyano-N-ethyl-6-fluoro-3-methoxy-N-methyl-benzenesulfonamide; (l) 2-cyano-3-difluoromethoxy-N,N-dimethylbenzenesulfon-amide; (m) 3-(difluoromethyl)-N-[2-(3,3-dimethylbutyl)phenyl]-1-methyl-1H-pyrazole-4-carboxamide; (n) N-ethyl-2,2-dimethylpropionamide-2-(2,6-dichloro-α,α,α-trifluoro-p-tolyl) hydrazone; (o) N-ethyl-2,2-dichloro-1-methylcyclopropane-carboxamide-2-(2,6-dichloro-α,α,α-trifluoro-p-tolyl) hydrazone nicotine; (p) O-{(E-)-[2-(4-chloro-phenyl)-2-cyano-1-(2-trifluoromethylphenyl)-vinyl]}S-methyl thiocarbonate; (q) (E)-N1-[(2-chloro-1,3-thiazol-5-ylmethyl)]-N2-cyano-N1-methylacetamidine; (r) 1-(6-chloropyridin-3-ylmethyl)-7-methyl-8-nitro-1,2,3,5,6,7-hexahydro-imidazo[1,2-a]pyridin-5-ol; (s) 4-[4-chlorophenyl-(2-butylidine-hydrazono)methyl)]phenyl mesylate; and (t) N-Ethyl-2,2-dichloro-1-methylcyclopropanecarboxamide-2-(2,6-dichloro-alpha,alpha,alpha-trifluoro-p-tolyl)hydrazone.
 44. A composition according to claim 1 further comprising a compound having one or more of the following modes of action: acetylcholinesterase inhibitor; sodium channel modulator; chitin biosynthesis inhibitor; GABA and glutamate-gated chloride channel antagonist; GABA and glutamate-gated chloride channel agonist; acetylcholine receptor agonist; acetylcholine receptor antagonist; MET I inhibitor; Mg-stimulated ATPase inhibitor; nicotinic acetylcholine receptor; Midgut membrane disrupter; oxidative phosphorylation disrupter, and ryanodine receptor (RyRs).
 45. A composition according to claim 1 further comprising a seed.
 46. A composition according to claim 1 further comprising a seed that has been genetically modified to express one or more specialized traits.
 47. A composition according to claim 1 wherein said composition is encapsulated inside, or placed on the surface of, a capsule.
 48. A composition according to claim 1 wherein said composition is encapsulated inside, or placed on the surface of, a capsule, wherein said capsule has a diameter of about 100-900 nanometers or about 10-900 microns.
 49. A process comprising applying a composition according to claim 1, to an area to control a pest, in an amount sufficient to control such pest.
 50. A process according to claim 49 wherein said pest is selected from beetles, earwigs, cockroaches, flies. aphids, scales, whiteflies, leafhoppers, ants, wasps, termites, moths, butterflies, lice, grasshoppers, locusts, crickets, fleas, thrips, bristletails, mites, ticks, nematodes, and symphylans.
 51. A process according to claim 49 wherein said pest is from the Phyla Nematoda or Arthropoda.
 52. A process according to claim 49 wherein said pest is from the Subphyla Chelicerata, Myriapoda, or Hexapoda.
 53. A process according to claim 49 wherein said pest is from the Class of Arachnida, Symphyla, or Insecta.
 54. A process according to claim 49 wherein said pest is from the Order Anoplura, Order Coleoptera, Order Dermaptera, Order Blattaria, Order Diptera, Order Hemiptera, Order Hymenoptera, Order Isoptera, Order Lepidoptera, Order Mallophaga, Order Orthoptera, Order Siphonaptera, Order Thysanoptera, Order Thysanura, Order Acarina, or Order Symphyla.
 55. A process according to claim 49 wherein said pest is MYZUPE or BEMITA.
 56. A process according to claim 49 wherein said amount is from about 0.01 grams per hectare to about 5000 grams per hectare.
 57. A process according to claim 49 wherein said amount is from about 0.1 grams per hectare to about 500 grams per hectare.
 58. A process according to claim 49 wherein said amount is from about 1 gram per hectare to about 50 grams per hectare.
 59. A process according to claim 49 wherein said area is an area where apples, corn, cotton, soybeans, canola, wheat, rice, sorghum, barley, oats, potatoes, oranges, alfalfa, lettuce, strawberries, tomatoes, peppers, crucifers, pears, tobacco, almonds, sugar beets, or beans, are growing, or the seeds thereof are going to be planted.
 60. A process according to claim 49 further comprising applying said composition to a genetically modified plant that has been genetically modified to express one or more specialized traits.
 61. A process according to claim 49 where said composition further comprise ammonium sulfate.
 62. A process comprising: orally administering; or topically applying; a composition according to claim 1, to a non-human animal, to control endoparasites, ectoparasites, or both.
 63. A process comprising applying a composition according to claim 1 to a plant to enhance the plant's health, yield, vigor, quality, or tolerance, at a time when pest activity is low.
 64. A process comprising reacting a compound of Formula 33.1 with a compound of Formula 33.2 to produce a compound of Formula 33.3 wherein said R₁, R₂, R₃, R₄, R₅, R₆, and R₈ are as defined in claim 1


65. A process comprising reacting a compound of Formula XXX with a compound of 